Benzo-fused heterocyclic derivatives useful as agonists of gpr120

ABSTRACT

The present invention is directed to benzo-fused heterocyclic derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by GPR120. More particularly, the compounds of the present invention are agonists of GPR120, useful in the treatment of, such as for example, Type II diabetes mellitus.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application61/783,118, filed on Mar. 14, 2013, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to benzo-fused heterocyclicderivatives, pharmaceutical compositions containing them and their usein the treatment of disorders and conditions modulated by GPR120. Moreparticularly, the compounds of the present invention are agonists ofGPR120, useful in the treatment of related diseases and disorders, suchas for example, Type II diabetes mellitus.

BACKGROUND OF THE INVENTION

A diabetes mellitus epidemic is unfolding across the globe with theWorld Health Organization (WHO) reporting a worldwide prevalence of 177million patients with diabetes. It is estimated that the incidence ofall forms of diabetes totals approximately 2.8% of the world population.The number of newly diagnosed diabetic patients is increasing by 4-5%per year. The total number of people with diabetes worldwide isprojected to rise to 366 million (4.4% prevalence) in 2030. Type 2diabetes accounts for approximately 95% of all diabetes cases. Long-termcomplications of type 2 diabetes include atherosclerosis, heart disease,stroke, end-stage renal disease, retinopathy leading to blindness, nervedamage, sexual dysfunction, frequent infections, and difficult-to-treatfoot ulcers, sometimes resulting in lower limb amputation. Diabetics aretwice as likely to develop cardiovascular disease or have a stroke, 2 to6 times more likely to have transient ischemic attacks, and 15 to 40times more likely to require lower-limb amputation compared with thegeneral population. The total estimated cost of diabetes in 2007 in theUS was $174 billion, including $116 billion in medical expenditures. Thelargest components of medical expenditures attributed to diabetes arehospital inpatient care (50% of total cost), diabetes medication andsupplies (12%), retail prescriptions to treat complications of diabetes(11%), and physician office visits (9%). This may be related to the lackof durable efficacy of current drug therapies for Type 2 diabetes (>50%Type 2 patients are not reaching the targeted blood glucose control withcurrent oral medications after 5 years of treatment). There is a generalconsensus that a considerable need exists for improved awareness,diagnosis and new, more effective, drug therapies for diabetes.

GLP-1 is secreted from specific cells in the colon following a meal andis a key regulator of glucose homeostasis, linking the gut, brain andpancreas. GLP-1 potentiates insulin secretion, reduces glucagonsecretion and preserves β-cell function whilst also improving satiety.Levels of post-prandial GLP-1 are reduced in type 2 diabetics anddramatically elevated following gastric by-pass surgery, contributing tothe amelioration of type 2 diabetes in these patients. Approaches thatprolong the half-life of GLP-1 (JANUVIA (Merck), GALVUS (Novartis)) oractivate the GLP-1 receptor (BYETTA (Amylin)) have been recentlyapproved for use in type 2 diabetes.

Hyperinsulinemia in patients with type 2 diabetes mellitus results fromperipheral insulin resistance, coupled with inadequate pancreaticinsulin secretion and elevated glucagon levels. There is a strongcorrelation between obesity and peripheral insulin resistance andhyperinsulinemia. Accumulation of free fatty acids in insulin responsivetissues other than fat (i.e. muscle and liver) results in tissue insulinresistance. Additionally, free fatty acids have a direct effect on thepancreas and in the colon and further stimulate glucose-dependentinsulin secretion and GLP-1 release with acute exposure whereas chronicexposure of free fatty acids impairs insulin secretion and becomes toxicto the β-cell. In the liver, hyperinsulinemia per se has been linked toexacerbating insulin resistance by increasing liver fatty acidaccumulation and hepatic glucose output creating a vicious cycle ofdisease progression. Current therapeutic strategies only partiallyaddress the complex pathology of free fatty acids in the exacerbation ofdiabetes. Agents that target both liver and pancreas function, directlyor indirectly via GLP-1 release, either individually or in combinationwith current treatment, could significantly improve blood glucosecontrol while maintaining β-cell function. Agents that potentiate GLP-1release also have the ability to reduce weight, providing additionalbenefits.

GPR120 is a seven transmembrane g-protein coupled receptor (GPCR) thatis predominantly expressed in the intestine and adipose. GPR120functions as a receptor for long chain free fatty acids (FFAs). AcuteFFA stimulation of GPR120 in GLP-1 expressing cell-lines amplifies GLP-1release. Administration of α-linolenic acid into the colon of miceincreases GLP-1 and potentiates insulin release following a glucosechallenge. In contrast to agonists of GPR40, the existing literaturesuggests that a GPR120 agonist would potentiate insulin secretion andreduce glucagon indirectly via GLP-1 release. GPR120 is also expressedin adipose, with expression induced during differentiation. Inhibitionof GPR120 expression in 3T3-L1 adipocytes has been shown to reduceadipocyte differentiation. The role of the receptor in the adipose or inthe taste cells of the tongue where it has also been found remainsunclear.

GPR120 is a Gq coupled GPCR that acts a receptor for long chain fattyacids. It belongs to a family of lipid binding GPCRs that include GPR40, 41, 43. Functionally, GPR120s closest homolog is GPR40. The clonedrat and mouse GPR120 receptors have been cloned and have >85% homologywith the human receptor. GPR120 signals through Gq to elevateintracellular Ca+2 levels as well as activate MAP kinase signaltransduction cascades. GPR120's activation of calcium flux and PKCactivation is most likely how FFAs contribute to the release GLP-1in theL-cell.

Although relatively little is known about GPR120 due to lack of potent,selective pharmacological tools or a documented metabolic phenotype ofGPR120 knockout mice, the potential to elevate GLP-1 from asmall-molecule perspective is attractive as a novel approach to unmetmedical need in the treatment of type 2 diabetes mellitus and relateddisorders. The beneficial effects of elevating GLP-1 are already wellvalidated in the clinic and in addition to improved glucose homeostasis,offer the potential of weight loss. Thus it is theorized that GPR120agonists may be complementary to existing diabetes therapies that affectliver insulin sensitivity and those that preserve β-cell function.

There remains a need for GPR120 agonists for the treatment of disordersincluding, but not limited to obesity, Type II diabetes mellitus,dyslipidemia, and the like.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

is selected from the group consisting of

R¹ is selected from the group consisting of cyano, C₁₋₆alkyl, -(hydroxysubstituted C₁₋₄alkyl), chloro substituted C₁₋₄alkyl, fluoro substitutedC₁₋₄alkyl, C₂₋₄alkenyl, chloro substituted C₂₋₄alkenyl, fluorosubstituted C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄alkyl)-O—(C₁₋₄alkyl),—(C₁₋₄alkyl)-SO—(C₁₋₄alkyl), —(C₁₋₄alkyl)-SO₂—(C₁₋₄alkyl),—(C₁₋₄alkyl)-NR^(A)R^(B), —(C₁₋₄alkyl)-NR^(A)—C(O)—(C₁₋₄alkyl),—(C₁₋₄alkyl)-NR^(A)—SO₂—(C₁₋₄alkyl), —C(O)OH, —C(O)O—(C₁₋₄alkyl),—C(O)—(C₁₋₄alkyl), —C(O)—NR^(A)R^(B), C₃₋₈cycloalkyl,—(C₁₋₄alkyl)-(C₃₋₈cycloalkyl), aryl and —(C₁₋₂alkyl)-(aryl); whereinR^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R² is selected from the group consisting of hydrogen, halogen andC₁₋₄alkyl;

R³ is selected from the group consisting of hydrogen, chloro and fluoro;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, halogen, cyano, C₁₋₄alkyl, chloro substituted C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, C₂₋₄alkenyl, chloro substitutedC₂₋₄alkenyl, fluoro substituted C₂₋₄alkenyl, C₂₋₄alkynyl, chlorosubstituted C₂₋₄alkynyl, fluoro substituted C₂₋₄alkynyl, C₁₋₄alkoxy,fluoro substituted C₁₋₄alkoxy, —O—(C₁₋₄alkyl)-O—(C₁₋₄alkyl),—(C₁₋₄alkyl)-O—(C₁₋₄alkyl), —(C₁₋₄alkyl)-SO₂—(C₁₋₄alkyl),—(C₂₋₄alkenyl)-SO₂—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), —O-(aryl) and—O—(C₁₋₂alkyl)-aryl; wherein R^(C) and R^(D) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl;

provided that at least one of R⁴ or R⁵ is selected from the groupconsisting of hydrogen, chloro and fluoro;

alternatively, wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of

W is selected from the group consisting of C(R⁹); wherein R⁹ is selectedfrom the group consisting of hydrogen, fluoro and bromo;

alternatively, wherein

W may be N;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen, halogen, cyano, C₁₋₆alkyl, chloro substituted C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, bromo substituted C₁₋₄alkyl, C₁₋₄alkoxyand fluoro substituted C₁₋₄alkoxy;

alternatively, wherein

and W is C(R⁹), R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is selected from the group consisting of hydrogen, halogen, cyano,C₁₋₆alkyl, chloro substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl,bromo substituted C₁₋₄alkyl, C₁₋₄alkoxy, fluoro substituted C₁₋₄alkoxyand —(C₁₋₄alkyl)—C(O)OH,

R⁰ is selected from the group consisting of —CH₂OH and —C(O)OH;

and pharmaceutically acceptable salts thereof.

The present invention is further directed to processes for thepreparation of the compounds of formula (I). The present invention isfurther directed to a product prepared according to the processdescribed herein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the product prepared accordingto the process described herein. An illustration of the invention is apharmaceutical composition made by mixing the product prepared accordingto the process described herein and a pharmaceutically acceptablecarrier. Illustrating the invention is a process for making apharmaceutical composition comprising mixing the product preparedaccording to the process described herein and a pharmaceuticallyacceptable carrier.

Exemplifying the invention are methods of treating a disorder modulatedby GPR120 (selected from the group consisting of obesity, obesityrelated disorders, impaired oral glucose tolerance, insulin resistance,Type II diabetes mellitus, metabolic syndrome, metabolic syndrome X,dyslipidemia, elevated LDL, elevated triglycerides, obesity inducedinflammation, osteoporosis and obesity related cardiovascular disorders)comprising administering to a subject in need thereof a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsdescribed above.

In an embodiment, the present invention is directed to a compound offormula (I) for use as a medicament. In another embodiment, the presentinvention is directed to a compound of formula (I) for use in thetreatment of a disorder modulated by GPR120 (selected from the groupconsisting of obesity, obesity related disorders, impaired oral glucosetolerance, insulin resistance, Type II diabetes mellitus, metabolicsyndrome, metabolic syndrome X, dyslipidemia, elevated LDL, elevatedtriglycerides, obesity induced inflammation, osteoporosis and obesityrelated cardiovascular disorders). In another embodiment, the presentinvention is directed to a composition comprising a compound of formula(I) for the treatment of a disorder modulated by GPR120 (selected fromthe group consisting of obesity, obesity related disorders, impairedoral glucose tolerance, insulin resistance, Type II diabetes mellitus,metabolic syndrome, metabolic syndrome X, dyslipidemia, elevated LDL,elevated triglycerides, obesity induced inflammation, osteoporosis andobesity related cardiovascular disorders).

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)obesity, (b) obesity related disorders, (c) impaired oral glucosetolerance, (d) insulin resistance, (e) Type II diabetes mellitus, (f)metabolic syndrome, (g) metabolic syndrome X, (h) dyslipidemia, (i)elevated LDL, (j) elevated triglycerides, (k) obesity inducedinflammation, (I) osteoporosis and (m) obesity related cardiovasculardisorders, in a subject in need thereof. In another example, the presentinvention is directed to a compound as described herein for use in amethods for treating a disorder selected from the group consisting ofobesity, obesity related disorders, impaired oral glucose tolerance,insulin resistance, Type II diabetes mellitus, metabolic syndrome,metabolic syndrome X, dyslipidemia, elevated LDL, elevatedtriglycerides, obesity induced inflammation, osteoporosis and obesityrelated cardiovascular disorders, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

R³, R⁴, R⁵, R⁶, R⁷, R⁸, W and R⁰ are as herein defined. The compounds ofthe present invention are GPR120 agonists useful in the treatment ofrelated disorders and diseases, including, obesity, obesity relateddisorders, impaired oral glucose tolerance, insulin resistance, Type IIdiabetes mellitus, metabolic syndrome, metabolic syndrome X,dyslipidemia, elevated LDL, elevated triglycerides, obesity inducedinflammation, osteoporosis and obesity related cardiovascular disorders;preferably, obesity, insulin resistance, Type II diabetes mellitus ordyslipidemia.

The compounds of formula (I) of the present invention have beenunexpectedly found not to induce P450 activity. More particularly, itwas unexpectedly found that substitution at the R⁴ and/or R⁵ positions,preferably at the R⁴ position, was most effective in achieving thisdesired effect.

In an embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of

In another embodiment, the present invention is directed to compounds offormula (I) wherein

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of

In an embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of cyano,C₁₋₆alkyl, -(hydroxy substituted C₁₋₄alkyl), fluoro substitutedC₁₋₄alkyl, C₂₋₄alkenyl, fluoro substituted C₂₋₄alkenyl, C₂₋₄alkynyl,—(C₁₋₄alkyl)-O—(C₁₋₄alkyl), —(C₁₋₄alkyl)-NR^(A)R^(B),—(C₁₋₄alkyl)-NR^(A)—C(O)—(C₁₋₄alkyl),—(C₁₋₄alkyl)-NR^(A)—SO₂—(C₁₋₄alkyl), —C(O)OH, —C(O)O—(C₁₋₄alkyl),—C(O)—(C₁₋₄alkyl), —C(O)—NR^(A)R^(B), C₃₋₆cycloalkyl,—(C₁₋₄alkyl)-(C₃₋₆cycloalkyl), phenyl and —(C₁₋₂alkyl)-(phenyl); whereinR^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R¹ is selectedfrom the group consisting of cyano, C₁₋₄alkyl, -(hydroxy substitutedC₁₋₂alkyl), fluoro substituted C₁₋₂alkyl, fluoro substitutedC₂₋₄alkenyl, —(C₁₋₂alkyl)-O—(C₁₋₂alkyl), —(C₁₋₂alkyl)-NR^(A)R^(B),—(C₁₋₂alkyl)-NR^(A)—C(O)—(C₁₋₂alkyl),—(C₁₋₂alkyl)-NR^(A)—SO₂—(C₁₋₂alkyl), —C(O)OH, —C(O)—(C₁₋₂alkyl),—C(O)—NR^(A)R^(B), C₅₋₆cycloalkyl, —(C₁₋₂alkyl)-(C₅₋₆cycloalkyl), phenyland —(C₁₋₂alkyl)-(phenyl); wherein R^(A) and R^(B) are eachindependently selected from the group consisting of hydrogen and methyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of cyano,methyl, ethyl, n-propyl, isopropyl, isopentyl, isobutyl, t-butyl,difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2-fluoro-ethen-1-yl,hydroxyl-methyl-, hydroxyl-ethyl-, methoxy-methyl-, methoxy-ethyl-,carboxy-, methyl-carbonyl-, aminocarbonyl-, dimethylamino-ethyl-,methyl-carbonyl-amino-ethyl-, methyl-sulfonyl-amino-ethyl-, cyclopentyl,cyclopentyl-methyl- and benzyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of cyano,methyl, ethyl, n-propyl, isopropyl, isobutyl, difluoromethyl,trifluoromethyl, 2,2-difluoroethyl, 2-fluoro-ethen-1-yl,hydroxyl-ethyl-, methoxy-methyl- and methoxy-ethyl-. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R¹ is selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, 2,2-difluoroethyl, 2-fluoro-ethen-1-yl, andmethoxy-methyl-. In another embodiment, the present invention isdirected to compounds of formula (I) wherein R¹ is selected from thegroup consisting of methyl, ethyl, n-propyl, 2,2-difluoroethyl and2-fluoro-ethen-1-yl. In another embodiment, the present invention isdirected to compounds of formula (I) wherein R¹ is selected from thegroup consisting of methyl, ethyl, n-propyl, 2,2-difluoroethyl and2-fluoro-ethen-1-yl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, halogen and C₁₋₄alkyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R² is selectedfrom the group consisting of hydrogen, halogen and C₁₋₂alkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, fluoro, bromo and methyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R² is selectedfrom the group consisting of hydrogen and methyl. In another embodiment,the present invention is directed to compounds of formula (I) wherein R²is hydrogen.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R³ is selected from the group consisting ofhydrogen, chloro and fluoro. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R³ is selectedfrom the group consisting of hydrogen and fluoro. In another embodiment,the present invention is directed to compounds of formula (I) wherein R³is hydrogen.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ and R⁵ are each independently selected from thegroup consisting of hydrogen, halogen, cyano, C₁₋₄alkyl, fluorosubstituted C₁₋₄alkyl, C₂₋₄alkenyl, fluoro substituted C₂₋₄alkenyl,C₂₋₄alkynyl, fluoro substituted C₂₋₄alkynyl, C₁₋₄alkoxy, fluorosubstituted C₁₋₄alkoxy, —O—(C₁₋₄alkyl)-O—(C₁₋₄alkyl),—(C₁₋₄alkyl)-O—C(₁₋₄alkyl), —C(₁₋₄alkyl)-SO₂—(C₁₋₄alkyl),—C(₂₋₄alkyl)-SO₂—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), —O-(phenyl) and—O—(C₁₋₂alkyl)-(phenyl); wherein R^(C) and R^(D) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl; providedthat at least one of R⁴ or R⁵ is selected from the group consisting ofhydrogen, chloro and fluoro. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, cyano, C₁₋₄alkyl, fluoro substituted C₁₋₂alkyl, C₂₋₄alkynyl,fluoro substituted C₂₋₄alkynyl, C₁₋₄alkoxy, fluoro substitutedC₁₋₄alkoxy, —O—(C₁₋₂alkyl)-O—(C₁₋₂alkyl), —(C₁₋₄alkyl)—SO₂—(C₁₋₂alkyl),—(C₂₋₄alkenyl)-SO₂—(C₁₋₂alkyl), —C(O)—NR^(C)R^(D), —O-(phenyl) and—O—(C₁₋₂alkyl)-(phenyl); wherein R^(C) and R^(D) are each independentlyselected from the group consisting of hydrogen and C₁₋₂alkyl; providedthat at least one of R⁴ or R⁵ is selected from the group consisting ofhydrogen, chloro and fluoro.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ and R⁵ are each independently selected from thegroup consisting of hydrogen, halogen, cyano, C₁₋₄alkyl, chlorosubstituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, C₂₋₄alkenyl, chlorosubstituted C₂₋₄alkenyl, fluoro substituted C₂₋₄alkenyl, C₂₋₄alkynyl,chloro substituted C₂₋₄alkynyl, fluoro substituted C₂₋₄alkynyl,C₁₋₄alkoxy, fluoro substituted C₁₋₄alkoxy, —O—(C₁₋₄alkyl)—O—(C₁₋₄alkyl),—C(₁₋₄alkyl)-O—(C₁₋₄alkyl), —(C₁₋₄alkyl)-SO₂—(C₁₋₄alkyl),—C(O)—NR^(C)R^(D), —O-(aryl) and —O—(C₁₋₂alkyl)-aryl; wherein R^(C) andR^(D) are each independently selected from the group consisting ofhydrogen and C₁₋₄alkyl; provided that at least one of R⁴ or R⁵ isselected from the group consisting of hydrogen, chloro and fluoro.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ and R⁵ are each independently selected from thegroup consisting of hydrogen, chloro, fluoro, bromo, iodo, methyl,ethyl, trifluoromethyl, 1,1-difluoroethyl, ethynyl, prop-1-yn-1-yl,3,3,3-trifluoroprop-1-yn-1-yl, methoxy, ethoxy, isopropyloxy,isobutyloxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,phenyloxy, benzyloxy, cyano, dimethylaminocarbonyl-, methoxy-ethoxy-,3-(methylsulfonyl)-prop-1-yl and 3-(methylsulfonyl)-prop-1-yn-1-yl;provided that at least one of R⁴ or R⁵ is selected from the groupconsisting of hydrogen, chloro and fluoro.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofhydrogen, chloro, fluoro, bromo, iodo, trifluoromethyl,1,1,-difluoroethyl, ethynyl, prop-1-yn-1-yl,3,3,3-trifluoroprop-1-yn-1-yl, ethoxy, difluoromethoxy,trifluoromethoxy, cyano, dimethylaminocarbonyl-,3-(methylsulfonyl)-prop-1-yl and 3-(methylsulfonyl)-prop-1-yn-1-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from group consisting of hydrogen,chloro, fluoro, bromo, iodo, ethynyl, trifluoromethyl, ethoxy,difluoromethoxy, trifluoromethoxy, prop-1-yn-1-yl and cyano. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R⁴ is selected from group consisting of hydrogen, chloro,fluoro, bromo, iodo, ethynyl, trifluoromethyl, difluoromethoxy,trifluoromethoxy, prop-1-yn-1-yl and cyano. In another embodiment, thepresent invention is directed to compounds of formula (I) wherein R⁴ isselected from group consisting of chloro, bromo, iodo, ethynyl,trifluoromethyl, difluoromethoxy, trifluoromethoxy and cyano.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁵ is selected from the group consisting ofhydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, isopropyloxy,isobutyloxy, 2,2,2-trifluoroethoxy, difluoromethoxy, phenyloxy,benzyloxy, methoxy-ethoxy- and 3-(methylsulfonyl)-prop-1-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁵ is selected from the group consisting ofhydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, isopropyloxy,isobutyloxy, 2,2,2-trifluoroethoxy, difluoromethoxy and methoxy-ethoxy-.In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁵ is selected from the group consisting ofhydrogen, methyl, ethyl, methoxy and difluoromethoxy.

In an embodiment, the present invention is directed to compounds offormula (I) wherein

and wherein R⁴ and R⁵ may be taken together with the carbon atoms towhich they are bound to form a ring structure selected from the groupconsisting of

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of

and wherein R⁴ and R⁵ may be taken together with the carbon atoms towhich they are bound to form a ring structure selected from the groupconsisting of

In another embodiment, the present invention is directed to compounds offormula (I) wherein alternatively, wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of

In another embodiment, the present invention is directed to compounds offormula (I) wherein alternatively, wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form

In an embodiment the present invention is directed to compounds offormula (I) wherein W is selected from the group consisting of CH, C(F)and C(Br). In another embodiment, the present invention is directed tocompounds of formula (I) wherein W is selected from the group consistingof CH and C(F). In another embodiment, the present invention is directedto compounds of formula (I) wherein W is CH. In another embodiment, thepresent invention is directed to compounds of formula (I) wherein W isN.

In an embodiment, the present invention is directed to compounds offormula (I) wherein

and wherein W may be N. In another embodiment, the present invention isdirected to compounds of formula (I) wherein

is selected from the group consisting of

and wherein W may be N.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen, halogen, cyano, C₁₋₆alkyl, fluorosubstituted C₁₋₄alkyl, C₁₋₄alkoxy and fluoro substituted C₁₋₄alkoxy. Inanother embodiment, the present invention is directed to compounds offormula (I) wherein R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen, halogen, C₁₋₆alkyl, fluoro substitutedC₁₋₂alkyl and cyano.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen, fluoro, methyl, n-propyl, isobutyl,isopentyl, trifluoromethyl and cyano.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁶ is selected from the group consisting ofhydrogen, fluoro, methyl and cyano. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R⁶ is selectedfrom the group consisting of hydrogen, fluoro and methyl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R⁶ is methyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁷ is selected from the group consisting ofhydrogen, fluoro, methyl, n-propyl, isobutyl, isopentyl andtrifluoromethyl. In another embodiment, the present invention isdirected to compounds of formula (I) wherein R⁷ is selected from thegroup consisting of hydrogen, fluoro, methyl, n-propyl, isopentyl andtrifluoromethyl. In another embodiment, the present invention isdirected to compounds of formula (I) wherein R⁷ is selected from thegroup consisting of fluoro, methyl, n-propyl and trifluoromethyl. Inanother embodiment, the present invention is directed to compounds offormula (I) wherein R⁷ is selected from the group consisting of fluoro,methyl and n-propyl. In another embodiment, the present invention isdirected to compounds of formula (I) wherein R⁷ is methyl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein

wherein W is C(R⁹) and wherein R⁶ and R⁷ may be taken together with thecarbon atoms to which they are bound to form

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of

wherein W is CH and wherein R⁶ and R⁷ may be taken together with thecarbon atoms to which they are bound to form

In an embodiment, the present invention is directed to compounds offormula (I) wherein R⁸ is selected from the group consisting ofhydrogen, halogen, cyano, C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl,C₁₋₄alkoxy, fluoro substituted C₁₋₄alkoxy and —(C₁₋₄alkyl)-C(O)OH. Inanother embodiment, the present invention is directed to compounds offormula (I) wherein R⁸ is selected from the group consisting ofhydrogen, C₁₋₂alkyl and fluoro substituted C₁₋₂alkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁸ is selected from the group consisting ofhydrogen, methyl and trifluoromethyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R⁸ is selectedfrom the group consisting of hydrogen and trifluoromethyl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R⁸ is hydrogen.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R⁰ is —CH₂OH. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R⁰ is —C(O)OH.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e.

R⁰, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, W, etc.) areindependently selected to be any individual substituent or any subset ofsubstituents selected from the complete list as defined herein.

In another embodiment of the present invention is any single compound orsubset of compounds selected from the representative compounds listed inTables 1-4 below. Representative compounds of the present invention areas listed in Table 1 to 4 below. Unless otherwise noted, wherein astereogenic center is present in the listed compound, the compound wasprepared as a mixture of stereo-isomers.

TABLE 1 Representative Compounds of Formula (I)

ID No

R³ R⁴ R⁵ R⁶ R⁷ R⁸  1 4-(2,3-dimethyl-benzofuryl) H H H F F H  27-(2-methyl-benzofuryl) H F H CH₃ CH₃ H  3 7-(2-ethyl-benzofuryl) H F HCH₃ CH₃ H  4 7-(2-trifluoro-methyl-benzofuryl) H F H CH₃ CH₃ H  57-(2-methyl-3-fluoro-benzofuryl) H F H CH₃ CH₃ H  64-(2-methyl-benzofuryl) H H H F F H  7 7-(1-methyl-indazolyl) H Cl H CH₃CH₃ H  8 7-(2-methyl-indazolyl) H Cl H CH₃ CH₃ H  97-(2-isopentyl-benzofuryl) H F H CH₃ CH₃ H  107-(2-methoxy-ethyl-benzofuryl) H F H CH₃ CH₃ H  117-(2-ethyl-benzofuryl) H Cl H CH₃ CH3 H  12 7-(2-ethyl-benzofuryl) HOCF₃ H CH₃ CH₃ H  13 7-(2-n-propyl-benzofuryl) H F H CH₃ CH₃ H  147-(2-hydroxy-methyl-benzofuryl) H F H CH₃ CH₃ H  157-(2-hydroxy-ethyl-benzofuryl) H F H CH₃ CH₃ H  167-(2-ethyl-benzofuryl) H F H F F H  18 7-(2-cyclopentyl-benzofuryl) H FH CH₃ CH₃ H  19 7-(2-cyclopentyl-methyl-benzofuryl) H F H CH₃ CH₃ H  207-(2-benzyl-benzofuryl) H F H CH₃ CH₃ H  217-(2-methoxy-methyl-benzofuryl) H F H CH₃ CH₃ H  227-(2-isopropyl-benzofuryl) H F H CH₃ CH₃ H  23 7-(2-isobutyl-benzofuryl)H F H CH₃ CH₃ H  24 7-(2-methyl-carbonyl-amino-ethyl-benzofuryl) H F HCH₃ CH₃ H  25 7-(2-methyl-sulfonyl-amino-ethyl-benzofuryl) H F H CH₃ CH₃H  26 7-(2-dimethyl-amino-ethyl-benzofuryl) H F H CH₃ CH₃ H  277-(2-t-butyl-benzofuryl) H F H CH₃ CH₃ H  29 7-(2-ethyl-benzofuryl) H—O-ethyl H CH₃ CH₃ H  31 7-(2-n-propyl-benzofuryl) H Cl H CH₃ CH₃ H  327-(2-difluoro-methyl-benzofuryl) H F H CH₃ CH₃ H  357-(2-n-propyl-benzofuryl) H OCF₃ H CH₃ CH₃ H  36 7-(2-methyl-benzofuryl)H OCF₃ H CH₃ CH₃ H  37 7-(2-n-propyl-benzofuryl) H CF₃ H CH₃ CH₃ H  387-(2-n-propyl-benzofuryl) H ethynyl H CH₃ CH₃ H  407-(2-ethyl-benzofuryl) H Cl CH₃ CH₃ CH₃ H  41 7-(2-n-propyl-benzofuryl)H Cl H cyano CH₃ H  42 7-(2-amino-carbonyl-benzofuryl) H F H CH₃ CH₃ H 43 7-(2-carboxy-benzofuryl) H F H CH₃ CH₃ H  44 7-(2-ethyl-benzofuryl)H Cl OCH₃ CH₃ CH₃ H  45 7-(2-ethyl-benzofuryl) H Br H CH₃ CH₃ H  467-(2-n-propyl-benzofuryl) H —C(O)—N(CH₃)₂ H CH₃ CH₃ H  477-(2-n-propyl-benzofuryl) H I H CH₃ CH₃ H  487-(2,3-dimethyl-benzofuryl) H F H CH₃ CH₃ H  49 7-(2-cyano-benzofuryl) HF H CH₃ CH₃ H  56 7-(2-methyl-carbonyl-benzofuryl) H F H CH₃ CH₃ H  577-(2-ethyl-benzofuryl) H difluoro-methoxy H CH₃ CH₃ H  587-(2-n-propyl-benzofuryl) H prop-1-yn-1-yl H CH₃ CH₃ H  597-(2-n-propyl-benzofuryl) H Cl H F F H  60 4-(2,3-dimethyl-benzofuryl) HH H CH₃ CH₃ H  61 7-(2-ethyl-benzofuryl) H Cl ethyl CH₃ CH₃ H  627-(2-ethyl-benzofuryl) H Cl ethoxy CH₃ CH₃ H  63 7-(2-ethyl-benzofuryl)H Cl methoxy-ethoxy- CH₃ CH₃ H  64 7-(2-ethyl-benzofuryl) H Cl2,2,2-trifluoro- CH₃ CH₃ H ethoxy  65 7-(2-ethyl-benzofuryl) H Cliso-propyl-oxy- CH₃ CH₃ H  66 7-(2-ethyl-benzofuryl) H H ethoxy CH₃ CH₃H  67 7-(2-ethyl-benzofuryl) H Cl isobutyl-oxy CH₃ CH₃ H  687-(2-ethyl-benzofuryl) H Cl benzyl-oxy- CH₃ CH₃ H  697-(2-ethyl-benzofuryl) H Cl difluoro-methoxy CH₃ CH₃ H  707-(2-ethyl-benzofuryl) H H difluoro-methoxy CH₃ CH₃ H  717-(2-methyl-benzofuryl) F OCF₃ F CH₃ CH₃ H  72 7-(2-n-propyl-benzofuryl)H 3,3,3-trifluoro-prop- H CH₃ CH₃ H 1-yn-1-yl  73 7-(2-ethyl-benzofuryl)H Cl phenyl-oxy- CH₃ CH₃ H  74 7-(2-methyl-benzofuryl) OCH₃ OCF₃ F F F H 75 7-(2-methyl-benzofuryl) F OCF₃ F F F H  76 7-(2-methyl-benzofuryl) Hdifluoro-methoxy H CH₃ CH₃ H  77 7-(2-n-propyl-benzofuryl) Hdifluoro-methoxy H CH₃ CH₃ H  78 7-(2-methyl-benzofuryl) H Cl H CH₃ CH₃H  79 7-(2-n-propyl-benzofuryl) H 1,1-difluoro-ethyl- H CH₃ CH₃ H  804-(2,3-dimethyl-benzofuryl) H Cl H CH₃ CH₃ H  81 4-(2-methyl-benzofuryl)H Cl H CH₃ CH₃ H  83 7-(2-methyl-benzofuryl) H prop-1-yn-1-yl H CH₃ CH₃H  84 7-(2-methyl-benzoxazolyl) H Cl H CH₃ CH₃ H  857-(2-methyl-benzofuryl) H Cl CH₃ CH₃ CH₃ H  877-(2-(2,2-difluoro-ethyl)-benzofuryl) H Cl H CH₃ CH₃ H  887-(2-(2-fluoro-ethen-1-yl)-benzofuryl) H Cl H CH₃ CH₃ H  917-(2-methyl-benzothienyl) H Cl H CH₃ CH₃ H  947-(2-hydroxy-ethyl-benzofuryl) H OCF₃ H CH₃ CH₃ H  954-(2-methyl-benzoxazolyl) H Cl H CH₃ CH₃ H  967-(2-(2,2-difluoroethyl)-benzofuryl) H OCF₃ H CH₃ CH₃ H  977-(2-(2-fluoro-ethen-1-yl)-benzofuryl) H OCF₃ H CH₃ CH₃ H  984-(2-methyl-benzothiazolyl) H Cl H CH₃ CH₃ H  99 7-(2-methyl-benzofuryl)H 3-(methyl-sulfonyl)- H CH₃ CH₃ H prop-1-yn-1-yl 1007-(2-methyl-benzofuryl) H 3-(methyl-sulfonyl)- H CH₃ CH₃ H prop-1-yl 1014-(2-methyl-benzothienyl) H Cl H CH₃ CH₃ H 1044-(2-t-butyl-benzothiazolyl) H Cl H CH₃ CH₃ H 1054-(2-ethyl-benzothiazolyl) H F H CH₃ CH₃ H 1064-(2-isopropyl-benzothiazolyl) H Cl H CH₃ CH₃ H 1074-(2-t-butyl-benzothiazolyl) H F H CH₃ CH₃ H 108 7-(2-methyl-benzofuryl)H Cl 3-(methyl-sulfonyl) CH₃ CH₃ H prop-1-yl 1094-(2-ethyl-benzothiazolyl) H Cl H CH₃ CH₃ H 1104-(2-isobutyl-benzothiazolyl) H Cl H CH₃ CH₃ H 1114-(2-isopropyl-benzothiazolyl) H F H CH₃ CH₃ H 1127-(2-methyl-benzofuryl) H OCF₃ H H CF₃ H 1154-(2-isobutyl-benzothiazolyl) H F H CH₃ CH₃ H 1174-(2-trifluoro-methyl-benzothiazolyl) H F H CH₃ CH₃ H 1184-(2-methyl-benzothiazolyl) H OCF₃ H CH₃ CH₃ H 1194-(2-trifluoro-methyl-benzothiazolyl) H Cl H CH₃ CH₃ H 1217-(2-methyl-benzothiazolyl) H Cl H CH₃ CH₃ H 122 7-(2-ethyl-benzofuryl)H cyano H CH₃ CH₃ H

In Table 2 which follows herein, the ring structures shown in thecolumns headed “R⁶ and R⁷ taken together” and “R⁴ and R⁵ taken together”are incorporated into the structure drawn at the head of the table, inthe orientation as drawn.

TABLE 2 Representative Compounds of Formula (I)

            ID No

            R⁴             R⁵           R⁶ and R⁷ taken together 527-(2-ethyl-benzofuryl) OCF₃ H

54 7-(2-ethyl-benzofuryl) Cl H

55 7-(2-methyl-benzofuryl) OCF₃ H

            ID No

          R⁴ and R⁵ taken together             R⁶             R⁷ 307-(2-ethyl-benzofuryl)

CH₃ CH₃ 82 7-(2-methyl-benzofuryl)

CH₃ CH₃ 89 7-(2-methyl-benzofuryl)

CH₃ CH₃ 90 7-(2-methyl-benzofuryl)

CH₃ CH₃

TABLE 3 Representative Compounds of Formula (I)

            ID No

            R⁴             R⁵             R⁶             R⁷            R⁹             R⁰  17 7-(2-ethyl-benzofuryl) F H F H F C(O)OH  507-(2-ethyl-benzofuryl) OCF₃ H H n-propyl F C(O)OH  517-(2-ethyl-benzofuryl) OCF₃ H H isopentyl F C(O)OH  537-(2-ethyl-benzofuryl) OCF₃ H H isobutyl F C(O)OH  867-(2-methyl-benzofuryl) Cl CH₃ F H F C(O)OH  927-(2-methyl-benzothienyl) Cl H F H F C(O)OH  937-(2-methyl-benzothienyl) Cl H F H F CH₂OH 102 4-(2-methyl-benzothienyl)Cl H F H F C(O)OH 103 4-(2-methyl-benzothienyl) Cl H F H F CH₂OH 1204-(2-methyl-3-bromo-benzofuryl) OCF₃ H CH₃ CH₃ Br C(O)OH

TABLE 4 Representative Compounds of Formula (I)

            ID No

            R⁴             R⁷             R⁸             R⁰  287-(2-ethyl-benzofuryl) F H CF₃ C(O)OH  33 7-(2-ethyl-benzofuryl) F CH₃ HC(O)OH  34 7-(2-n-propyl-benzofuryl) Cl CH₃ H C(O)OH 1237-(2-ethyl-benzofuryl) F H CH₃ C(O)OH

In another embodiment, the present invention is directed to one or morecompounds independently selected from the compounds listed in Table 5,below.

TABLE 5 Representative Compounds of the Present Invention Synthesis IDExample No. Compound name No. 13-{4-[(2,3-Dimethyl-1-benzofuran-4-yl)methoxy]- 862,3-difluorophenyl}propanoic acid 23-{4-[(5-Fluoro-2-methyl-1-benzofuran-7- 1yl)methoxy]-2,3-dimethylphenyl}propanoic acid 33-{4-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]- 832,3-dimethylphenyl}propanoic acid 43-(4-{[5-Fluoro-2-(trifluoromethyl)-1-benzofuran-7- 84yl]methoxy}-2,3-dimethylphenyl)propanoic acid 53-{4-[(3,5-Difluoro-2-methyl-1-benzofuran-7- 85yl)methoxy]-2,3-dimethylphenyl}propanoic acid 63-{2,3-Difluoro-4-[(2-methyl-1-benzofuran-4- 87yl)methoxy]phenyl}propanoic acid 73-{4-[(5-Chloro-1-methyl-1H-indazol-7-yl)methoxy]- 812,3-dimethylphenyl}propanoic acid 83-{4-[(5-Chloro-2-methyl-2H-indazol-7-yl)methoxy]- 822,3-dimethylphenyl}propanoic acid 93-(4-{[5-Fluoro-2-(3-methylbutyl)-1-benzofuran-7- 2yl]methoxy}-2,3-dimethylphenyl)propanoic acid 103-(4-{[5-Fluoro-2-(2-methoxyethyl)-1-benzofuran-7- 3yl]methoxy}-2,3-dimethylphenyl)propanoic acid 113-{4-[(5-Chloro-2-ethyl-1-benzofuran-7-yl)methoxy]- 882,3-dimethylphenyl}propanoic acid 123-(4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7- 89yl]methoxy}-2,3-dimethylphenyl)propanoic acid 133-{4-[(5-Fluoro-2-propyl-1-benzofuran-7- 4yl)methoxy]-2,3-dimethylphenyl}propanoic acid 143-(4-{[5-Fluoro-2-(hydroxymethyl)-1-benzofuran-7- 5yl]methoxy}-2,3-dimethylphenyl)propanoic acid 153-(4-{[5-Fluoro-2-(2-hydroxyethyl)-1-benzofuran-7- 6yl]methoxy}-2,3-dimethylphenyl)propanoic acid 163-{4-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]- 902,3-difluorophenyl}propanoic acid 173-{4-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]- 913,5-difluorophenyl}propanoic acid 183-{4-[(2-Cyclopentyl-5-fluoro-1-benzofuran-7- 7yl)methoxy]-2,3-dimethylphenyl}propanoic acid 193-(4-{[2-(Cyclopentylmethyl)-5-fluoro-1-benzofuran- 87-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 203-{4-[(2-Benzyl-5-fluoro-1-benzofuran-7- 9yl)methoxy]-2,3-dimethylphenyl}propanoic acid 213-(4-{[5-Fluoro-2-(methoxymethyl)-1-benzofuran-7- 10yl]methoxy}-2,3-dimethylphenyl)propanoic acid 223-(4-{[5-Fluoro-2-(1-methylethyl)-1-benzofuran-7- 11yl]methoxy}-2,3-dimethylphenyl)propanoic acid 233-(4-{[5-Fluoro-2-(2-methylpropyl)-1-benzofuran-7- 12yl]methoxy}-2,3-dimethylphenyl)propanoic acid 243-[4-({2-[2-(Acetylamino)ethyl]-5-fluoro-1- 13benzofuran-7-yl}methoxy)-2,3- dimethylphenyl}propanoic acid 253-{4-[(5-Fluoro-2-{2-[(methylsulfonyl)amino]ethyl}-1- 14benzofuran-7-yl)methoxy]-2,3- dimethylphenyl}propanoic acid 263-[4-({2-[2-(Dimethylamino)ethyl]-5-fluoro-1- 15benzofuran-7-yl}methoxy)-2,3- dimethylphenyl}propanoic acid 273-{4-[(2-tert-Butyl-5-fluoro-1-benzofuran-7- 16yl)methoxy]-2,3-dimethylphenyl}propanoic acid 283-{6-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]- 922-(trifluoromethyl)pyridin-3-yl}propanoic acid 293-{4-[(5-Ethoxy-2-ethyl-1-benzofuran-7- 17yl)methoxy]-2,3-dimethylphenyl}propanoic acid 303-{4-[(6-Ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2- 93 b:4,5-b′]difuran-4-yl)methoxy]-2,3- dimethylphenyl}propanoic acid 313-{4-[(5-Chloro-2-propyl-1-benzofuran-7- 94yl)methoxy]-2,3-dimethylphenyl}propanoic acid 323-(4-{[2-(Difluoromethyl)-5-fluoro-1-benzofuran-7- 95yl]methoxy}-2,3-dimethylphenyl)propanoic acid 333-{6-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]- 964-methylpyridin-3-yl}propanoic acid 343-{6-[(5-Chloro-2-propyl-1-benzofuran-7- 97yl)methoxy]-4-methylpyridin-3-yl}propanoic acid 353-(2,3-Dimethyl-4-{[2-propyl-5-(trifluoromethoxy)-1- 98benzofuran-7-yl]methoxy}phenyl)propanoic acid 363-(2,3-Dimethyl-4-{[2-methyl-5-(trifluoromethoxy)-1- 99benzofuran-7-yl]methoxy}phenyl)propanoic acid 373-(2,3-Dimethyl-4-{[2-propyl-5-(trifluoromethyl)-1- 18benzofuran-7-yl]methoxy}phenyl)propanoic acid 383-{4-[(5-Ethynyl-2-propyl-1-benzofuran-7- 19yl)methoxy]-2,3-dimethylphenyl}propanoic acid 403-{4-[(5-Chloro-2-ethyl-6-methyl-1-benzofuran-7- 20yl)methoxy]-2,3-dimethylphenyl}propanoic acid 413-{4-[(5-Chloro-2-propyl-1-benzofuran-7- 100yl)methoxy]-3-cyano-2-methylphenyl}propanoic acid 423-{4-[(2-Carbamoyl-5-fluoro-1-benzofuran-7- 21yl)methoxy]-2,3-dimethylphenyl}propanoic acid 437-{[4-(2-Carboxyethyl)-2,3- 22dimethylphenoxy]methyl}-5-fluoro-1-benzofuran-2- carboxylic acid 443-{4-[(5-Chloro-2-ethyl-6-methoxy-1-benzofuran-7- 23yl)methoxy]-2,3-dimethylphenyl}propanoic acid 453-{4-[(5-Bromo-2-ethyl-1-benzofuran-7-yl)methoxy]- 1012,3-dimethylphenyl}propanoic acid 463-(4-{[5-(Dimethylcarbamoyl)-2-propyl-1- 24benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 473-{4-[(5-Iodo-2-propyl-1-benzofuran-7-yl)methoxy]- 252,3-dimethylphenyl}propanoic acid 483-{4-[(5-Fluoro-2,3-dimethyl-1-benzofuran-7- 102yl)methoxy]-2,3-dimethylphenyl}propanoic acid 493-{4-[(2-Cyano-5-fluoro-1-benzofuran-7- 26yl)methoxy]-2,3-dimethylphenyl}propanoic acid 503-(4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7- 27yl]methoxy}-5-fluoro-2-propylphenyl)propanoic acid 513-[4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7- 28yl]methoxy}-5-fluoro-2-(3- methylbutyl)phenyl]propanoic acid 523-(7-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7- 29yl]methoxy}-2,3-dihydro-1H-inden-4-yl)propanoic acid 533-[4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7- 30yl]methoxy}-5-fluoro-2-(2- methylpropyl)phenyl]propanoic acid 543-{7-[(5-Chloro-2-ethyl-1-benzofuran-7-yl)methoxy]- 312,3-dihydro-1H-inden-4-yl}propanoic acid 553-(7-{[2-Methyl-5-(trifluoromethoxy)-1-benzofuran- 1037-yl]methoxy}-2,3-dihydro-1H-inden-4-yl)propanoic acid 563-{4-[(2-Acetyl-5-fluoro-1-benzofuran-7- 32yl)methoxy]-2,3-dimethylphenyl}propanoic acid 573-(4-{[5-(Difluoromethoxy)-2-ethyl-1-benzofuran-7- 33yl]methoxy}-2,3-dimethylphenyl)propanoic acid 583-{2,3-Dimethyl-4-[(2-propyl-5-prop-1-yn-1-yl-1- 34benzofuran-7-yl)methoxy}phenyl}propanoic acid 593-{4-[(5-Chloro-2-propyl-1-benzofuran-7- 104yl)methoxy]-2,3-difluorophenyl}propanoic acid 603-{4-[(2,3-Dimethyl-1-benzofuran-4-yl)methoxy]- 1052,3-dimethylphenyl}propanoic acid 613-{4-[(5-Chloro-2,6-diethyl-1-benzofuran-7- 35yl)methoxy]-2,3-dimethylphenyl}propanoic acid 623-{4-[(5-Chloro-6-ethoxy-2-ethyl-1-benzofuran-7- 36yl)methoxy]-2,3-dimethylphenyl}propanoic acid 633-(4-{[5-Chloro-2-ethyl-6-(2-methoxyethoxy)-1- 37benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 643-(4-{[5-Chloro-2-ethyl-6-(2,2,2-trifluoroethoxy)-1- 38benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 653-(4-{[5-Chloro-2-ethyl-6-(1-methylethoxy)-1- 39benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 663-{4-[(6-Ethoxy-2-ethyl-1-benzofuran-7- 40yl)methoxy]-2,3-dimethylphenyl}propanoic acid 673-(4-{[5-Chloro-2-ethyl-6-(2-methylpropoxy)-1- 41benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 683-(4-{[6-(Benzyloxy)-5-chloro-2-ethyl-1-benzofuran- 427-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 693-(4-{[5-Chloro-6-(difluoromethoxy)-2-ethyl-1- 43benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 703-(4-{[6-(Difluoromethoxy)-2-ethyl-1-benzofuran-7- 44yl]methoxy}-2,3-dimethylphenyl)propanoic acid 713-(4-{[4,6-Difluoro-2-methyl-5-(trifluoromethoxy)-1- 106benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 723-(2,3-Dimethyl-4-{[2-propyl-5-(3,3,3-trifluoroprop- 451-yn-1-yl)-1-benzofuran-7- yl]methoxy}phenyl)propanoic acid 733-{4-[(5-Chloro-2-ethyl-6-phenoxy-1-benzofuran-7- 46yl)methoxy]-2,3-dimethylphenyl}propanoic acid 743-(2,3-Difluoro-4-{[6-fluoro-4-methoxy-2-methyl-5- 107(trifluoromethoxy)-1-benzofuran-7- yl]methoxy}phenyl)propanoic acid 753-(4-{[4,6-Difluoro-2-methyl-5-(trifluoromethoxy)-1- 108benzofuran-7-yl]methoxy}-2,3- difluorophenyl)propanoic acid 763-(4-{[5-(Difluoromethoxy)-2-methyl-1-benzofuran- 477-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 773-(4-{[5-(Difluoromethoxy)-2-propyl-1-benzofuran- 487-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 783-{4-[(5-Chloro-2-methyl-1-benzofuran-7- 49yl)methoxy]-2,3-dimethylphenyl}propanoic acid 793-(4-{[5-(1,1-Difluoroethyl)-2-propyl-1-benzofuran- 507-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 803-{4-[(6-Chloro-2,3-dimethyl-1-benzofuran-4- 109yl)methoxy]-2,3-dimethylphenyl}propanoic acid 813-{4-[(6-Chloro-2-methyl-1-benzofuran-4- 110yl)methoxy]-2,3-dimethylphenyl}propanoic acid 823-{2,3-Dimethyl-4-[(6-methylfuro[2,3- 51f][1,3]benzodioxol-4-yl)methoxy]phenyl}propanoic acid 833-{2,3-Dimethyl-4-[(2-methyl-5-prop-1-yn-1-yl-1- 52benzofuran-7-yl)methoxy]phenyl}propanoic acid 843-{4-[(5-Chloro-2-methyl-1,3-benzoxazol-7- 111yl)methoxy]-2,3-dimethylphenyl}propanoic acid 853-{4-[(5-Chloro-2,6-dimethyl-1-benzofuran-7- 53yl)methoxy]-2,3-dimethylphenyl}propanoic acid 863-{4-[(5-Chloro-2,6-dimethyl-1-benzofuran-7- 54yl)methoxy]-3,5-difluorophenyl}propanoic acid 873-(4-{[5-Chloro-2-(2,2-difluoroethyl)-1-benzofuran- 1127-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 883-(4-((5-Chloro-2-(2-fluorovinyl)benzofuran-7- 77yl)methoxy)-2,3-dimethylphenyl)propanoic acid 893-{4-[(2,2-Difluoro-6-methylfuro[2,3- 55f][1,3]benzodioxol-4-yl)methoxy]-2,3- dimethylphenyl}propanoic acid 903-{2,3-Dimethyl-4-[(7-methyl-2,3-dihydrofuro[2,3- 56g][1,4]benzodioxin-5-yl)methoxy]phenyl}propanoic acid 913-{4-[(5-Chloro-2-methyl-1-benzothiophen-7- 57yl)methoxy]-2,3-dimethylphenyl}propanoic acid 923-{4-[(5-Chloro-2-methyl-1-benzothiophen-7- 58yl)methoxy]-3,5-difluorophenyl}propanoic acid 933-{4-[(5-Chloro-2-methyl-1-benzothiophen-7- 59yl)methoxy]-3,5-difluorophenyl}propan-1-ol 943-(4-{[2-(2-Hydroxyethyl)-5-(trifluoromethoxy)-1- 113benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 953-{4-[(6-Chloro-2-methyl-1,3-benzoxazol-4- 114yl)methoxy]-2,3-dimethylphenyl}propanoic acid 963-(4-{[2-(2,2-Difluoroethyl)-5-(trifluoromethoxy)-1- 115benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 973-(4-{[2-(2-Fluoroethenyl)-5-(trifluoromethoxy)-1- 116benzofuran-7-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 983-{4-[(6-Chloro-2-methyl-1,3-benzothiazol-4- 117yl)methoxy]-2,3-dimethylphenyl}propanoic acid 993-[2,3-Dimethyl-4-({2-methyl-5-[3- 60(methylsulfonyl)prop-1-yn-1-yl]-1-benzofuran-7-yl}methoxy)phenyl]propanoic acid 100 3-[2,3-Dimethyl-4-({2-methyl-5-[3-61 (methylsulfonyl)propyl]-1-benzofuran-7- yl}methoxy)phenyl]propanoicacid 101 3-{4-[(6-Chloro-2-methyl-1-benzothiophen-4- 62yl)methoxy]-2,3-dimethylphenyl}propanoic acid 1023-{4-[(6-Chloro-2-methyl-1-benzothiophen-4- 63yl)methoxy]-3,5-difluorophenyl}propanoic acid 1033-{4-[(6-Chloro-2-methyl-1-benzothiophen-4- 64yl)methoxyl-3,5-difluorophenyl}propan-1-ol 1043-{4-[(2-tert-Butyl-6-chloro-1,3-benzothiazol-4- 65yl)methoxy]-2,3-dimethylphenyl}propanoic acid 1053-{4-[(2-Ethyl-6-fluoro-1,3-benzothiazol-4- 66yl)methoxy]-2,3-dimethylphenyl}propanoic acid 1063-(4-{[6-chloro-2-(1-methylethyl)-1,3-benzothiazol- 674-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 1073-{4-[(2-tert-butyl-6-fluoro-1,3-benzothiazol-4- 68yl)methoxy]-2,3-dimethylphenyl}propanoic acid 1083-[4-({5-Chloro-2-methyl-6-[3- 69(methylsulfonyl)propyl]-1-benzofuran-7-yl}methoxy)-2,3-dimethylphenyl]propanoic acid 1093-{4-[(6-Chloro-2-ethyl-1,3-benzothiazol-4- 70yl)methoxy]-2,3-dimethylphenyl}propanoic acid 1103-(4-{[6-Chloro-2-(2-methylpropyl)-1,3- 71benzothiazol-4-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 1113-(4-{[6-Fluoro-2-(1-methylethyl)-1,3-benzothiazol- 724-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 1123-[4-{[2-Methyl-5-(trifluoromethoxy)-1-benzofuran- 737-yl]methoxy}-2-(trifluoromethyl)phenyl]propanoic acid 1153-(4-{[6-Fluoro-2-(2-methylpropyl)-1,3- 76benzothiazol-4-yl]methoxy}-2,3- dimethylphenyl)propanoic acid 1173-(4-{[6-Fluoro-2-(trifluoromethyl)-1,3-benzothiazol- 784-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 1183-(2,3-Dimethyl-4-{[2-methyl-6-(trifluoromethoxy)- 1181,3-benzothiazol-4-yl]methoxy}phenyl)propanoic acid 1193-(4-{[6-Chloro-2-(trifluoromethyl)-1,3-benzothiazol- 794-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 1203-(5-Bromo-4-{[3-bromo-2-methyl-5- 119(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoic acid 1213-{4-[(5-Chloro-2-methyl-1,3-benzothiazol-7- 80yl)methoxy]-2,3-dimethylphenyl}propanoic acid 1223-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2- 75methylpyridin-3-yl)propanoic acid 1233-(4-((5-cyano-2-ethylbenzofuran-7-yl)methoxy)- 742,3-dimethylphenyl)propanoic acid

In an embodiment, the present invention is directed to compounds offormula (I) selected from the group consisting of3-{4-[(5-Chloro-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid;3-(2,3-Dimethyl-4-{[2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid;3-(7-{[2-Methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dihydro-1H-inden-4-yl)propanoicacid;3-{4-[(5-Chloro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid;3-{4-[(5-Chloro-2,6-dimethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid;3-(4-{[2-(2-Fluoroethenyl)-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid;3-{4-[(6-Chloro-2-methyl-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid; and pharmaceutically acceptable salts thereof.

In an embodiment, the present invention is directed to a compound offormula (I); wherein the compound of formula has a measured EC₅₀according to the β-arrestin A procedure taught in Biological Example 1,which follows herein or less than about 1.0 mM, preferably less thanabout 0.500 mM, more preferably less than about 0.200 mM, morepreferably less than about 0.100 mM, more preferably less than about0.050 mM.

In an embodiment, the present invention is directed to a compound offormula (I); wherein the compound of formula has a measured EC₅₀according to the Calcium A procedure taught in Biological Example 2,which follows herein or less than about 1.0 mM, preferably less thanabout 0.500 mM, more preferably less than about 0.200 mM, morepreferably less than about 0.100 mM, more preferably less than about0.050 mM.

Definitions

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl and the like. Unless otherwisenoted, the term “C_(X-Y)alkyl” wherein X and Y are integers shallinclude straight and branched chain composition of between X and Ycarbon atoms. For example, “C₁₋₄alkyl” shall include straight andbranched chain composition of between 1 and 4 carbon atoms, includingmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.

One skilled in the art will recognize that the term “—(C₁alkyl)-” shalldenote any C₁₋₄alkyl carbon chain as herein defined, wherein saidC₁₋₄alkyl chain is divalent and is further bound through two points ofattachment, preferably through two terminal carbon atoms.

As used herein, unless otherwise noted, the term “fluoro substitutedC₁₋₄alkyl” shall mean any C₁₋₄alkyl group as defined above substitutedwith at least one fluoro atom, preferably substituted with one to threefluoro atoms. Suitable examples include but are not limited to —CF₃,—CH₂—CF₃, —CF₂—CF₂—CF₂—CF₃, —CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “chloro substitutedC₁₋₄alkyl” shall mean any C₁₋₄alkyl group as defined above substitutedwith at least one chloro atom, preferably substituted with one to threechloro atoms. Suitable examples include but are not limited to —CCl₃,—CH₂—CCl₃, —CCl₂—CCl₂—CCl₂—CCl₃, —CCl₂—CCl₃, and the like.

As used herein, unless otherwise noted, the term “bromo substitutedC₁₋₄alkyl” shall mean any C₁₋₄alkyl group as defined above substitutedwith at least one bromo atom, preferably substituted with one to threebromo atoms. Suitable examples include but are not limited to —CH₂Br,—CH₂—CBr₃, —CH₂—CH₂—CH₂—CH₂Br, —CH(Br)—CH₃, and the like.

As used herein, unless otherwise noted, the term “hydroxy substitutedC₁₋₄alkyl” shall mean C₁₋₄alkyl group as defined above substituted withat least one hydroxy group. In an embodiment, the C₁₋₄alkyl group issubstituted with one hydroxy group. In another embodiment, the C₁₋₄alkylgroup is substituted with a hydroxy group at the terminal carbon.Suitable examples include, but are not limited to, —CH₂(OH),—CH₂—CH₂—OH, —CH₂—CH(OH)—CH₃, —CH₂—CH₂—CH₂—OH, and the like.

As used herein, the term “alkenyl” whether used alone or as part of asubstituent group, include straight and branched carbon chainscontaining at least one double bond, preferably one double bond. Unlessotherwise noted, the term “C_(X-Y)alkenyl” wherein X and Y are integersshall include straight and branched chain composition containing atleast one double bond of between X and Y carbon atoms. For example,“C₂₋₄alkenyl” shall include straight and branched chain composition ofbetween 2 and 4 carbon atoms containing at least one double bong,including for example, —CH═CH₂, —CH₂—CH═CH₂, —CH═CH—CH₃,—CH₂—CH₂—CH═CH₂, —CH₂—CH═CH—CH₃, —CH═CH—CH₂—CH₃, and the like.

As used herein, unless otherwise noted, the term “fluoro substitutedC₂₋₄alkenyl” shall mean any C₂₋₄alkenyl group as defined abovesubstituted with at least one fluoro atom, preferably substituted withone to three fluoro atoms. Suitable examples include but are not limitedto 2-fluoro-ethenyl, and the like.

As used herein, unless otherwise noted, the term “chloro substitutedC₂₋₄alkenyl” shall mean any C₂₋₄alkenyl group as defined abovesubstituted with at least one chloro atom, preferably substituted withone to three chloro atoms. Suitable examples include but are not limitedto 2-chloro-ethenyl, and the like.

As used herein, the term “alkynyl” whether used alone or as part of asubstituent group, include straight and branched carbon chainscontaining at least one triple bond, preferably one triple bond. Unlessotherwise noted, the term “C_(X-Y)alkynyl” wherein X and Y are integersshall include straight and branched chain composition containing atleast one triple bond of between X and Y carbon atoms. For example,“C₂₋₄alkynyl” shall include straight and branched chain composition ofbetween 2 and 4 carbon atoms containing at least one double bong,including for example, —CCH₂, —CH₂—CCH₂, —CC—CH₃, —CH₂—CH₂—CCH,—CH₂—CC—CH₃, —CC—CH₂—CH₃, and the like.

As used herein, unless otherwise noted, the term “fluoro substitutedC₂₋₄alkynyl” shall mean any C₂₋₄alkynyl group as defined abovesubstituted with at least one fluoro atom, preferably substituted withone to three fluoro atoms. Suitable examples include but are not limitedto 3-fluoro-prop-1-yn-1-yl, and the like.

As used herein, unless otherwise noted, the term “chloro substitutedC₂₋₄alkynyl” shall mean any C₂₋₄alkynyl group as defined abovesubstituted with at least one chloro atom, preferably substituted withone to three chloro atoms. Suitable examples include but are not limitedto 3-chloro-prop-1-yn-1-yl, and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like. Unless otherwise noted, the term“C_(X-Y)alkoxy” wherein X and Y are integers shall include an oxygenether radical as described above of between X and Y carbon atoms. Forexample, “C₁₋₄alkoxy” shall include oxygen ether radicals of between 1and 4 carbon atoms, including methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy and t-butoxy.

One skilled in the art will recognize that the term “—(C₁₋₄alkoxy)-”shall denote any oxygen ether radicals of between 1 and 4 carbon atomsas herein defined, wherein said C₁₋₄alkoxy is divalent and is furtherbound through two points of attachment, preferably through two terminalcarbon atoms.

As used herein, unless otherwise noted, the term “fluoro substitutedC₁₋₄alkoxy” shall mean any C₁₋₄alkoxy group as defined above substitutedwith at least one fluoro atom, preferably substituted with one to threefluoro atoms. Suitable examples include but are not limited to —O—CF₃,—O—CH₂—CF₃, —O—CF₂—CF₂—CF₂—CF₃, —O—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “C₃₋₈cycloalkyl” shallmean any stable 3-8 membered monocyclic, saturated ring system, forexample cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl,fluorenyl, and the like. In an embodiment, the aryl group is phenyl ornaphthyl, preferably phenyl.

When a particular group is “substituted” (e.g., C₁₋₄alkyl, C₂₋₄alkenyl,C₂-C₄alkynyl, C₅₋₆cycloalkyl, aryl, etc.), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

As used herein, the notation “*” shall denote the presence of astereogenic center.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

Furthermore, it is intended that within the scope of the presentinvention, any element, in particular when mentioned in relation to acompound of formula (I), shall comprise all isotopes and isotopicmixtures of said element, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, a reference to hydrogen includes within its scope ¹H,²H (D), and ³H (T). Similarly, references to carbon and oxygen includewithin their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. Theisotopes may be radioactive or non-radioactive. Radiolabelled compoundsof formula (I) may comprise a radioactive isotope selected from thegroup of ³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and⁸²Br. Preferably, the radioactive isotope is selected from the group of³H, ¹¹C and ¹⁸F.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   -   AcOH=Acetic acid    -   ADDP=1,1′-(azodicarbonyl)dipiperidine    -   AlBN=Azobisisobutyronitrile    -   BrettPhos=palladium        2-(dicyclohexylphosphino)3,6-[(COD)Pd(CH₂TMS)₂]        dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl    -   Bu₃P=Tributylphosphine    -   BuLi=Butyl lithium    -   n-BuLi=n-Butyl lithium    -   Sec-BuLi=sec-Butyl lithium    -   t-BuLi=tert-butyl lithium    -   Cu(OAc)₂=Copper Acetate    -   DAST in [C_(8min)][PF₆]=Diethylaminosulfur trifluoride in        1-methyl-3-octylimidazolium hexafluorophosphate    -   DCE=Dichloroethane    -   DCE=Dichloroethane    -   DCM=Dichloromethane    -   DEA=diethylamine    -   DEAD=Diethylazodicarboxylate    -   DIBAL or DIBAL-H=Diisobutylaluminium hydride    -   DIAD=Diisopropylazodicarboxylate    -   DIBAL or DIBAL-H=Diisobutylaluminium hydride    -   DIPEA or DIEA=Diisopropylethylamine    -   DMA=Dimethyl adipate    -   DMAP=4-N,N-Dimethylaminopyridine    -   DME=Dimethylether    -   DMF=N,N-Dimethylformamide    -   DMP=Dess-Martin periodinane    -   DMSO=Dimethylsulfoxide    -   dppf=1,1′-Bis(diphenylphosphino)ferrocene    -   Et₂NH=Diethylamine    -   Et₂O=Diethyl ether    -   Et₃N or TEA=Triethylamine    -   EtOAc=Ethyl acetate    -   EtOH=Ethanol    -   EtOMesylate or=Ethyl methanesulonate EtOMs    -   EtOTriflate or EtOTf=Ethyl trifluoromethanesulfonate    -   hep=heptane    -   HPLC=High Pressure Liquid Chromatography    -   LAH=Lithium aluminum hydride    -   LDA=Lithium diisopropylamide    -   LDL=Low density Lipoprotein    -   Li(Bu^(t)O)₃AlH=Lithium tri-tert-butoxyaluminum hydride    -   mCPBA or m-CPBA=meta-Chloroperoxybenzoic add    -   Me=Methyl (i.e. —CH₃)    -   MeOH=Methanol    -   Mesyl=Methylsulfonyl    -   MOM=Methoxy methyl ether    -   MsCl=Mesyl chloride    -   MsOH=Methanse sulfonic acid    -   MTBE=Methyl t-butyl ether    -   NAHMDS=Sodium bis(trimethylsilyl)amide    -   NBS=N-Bromosuccinimide    -   n-BuLi=n-Butyl Lithium    -   NCS=N-Chlorosuccinimide    -   NMP=N-methyl-2-pyrrolidinone    -   Pd/C=Palladium on Carbon Catalyst    -   Pd₂(dba)₃=Tris(dibenzylidene acetone)dipalladium(0)    -   Pd(dppe)Cl₂=Palladium 1,2-Bis(diphenylphosphino)ethane        dichloride    -   Pd(dppf)Cl₂=[1,1′-Bis(diphenylphosphino)        ferrocene]dichloropalladium(II)    -   Pd₂(OAc)₂=Palladium(II)acetate    -   Pd(PPh₃)₂Cl₂ or=Bis(triphenylphosphine)palladium (II)        PdCl₂(Ph₃P)₂ chloride    -   Pd(PPh₃)₄=Tetrakistriphenylphosphine palladium (0)    -   PE=Petroleum ether    -   PPA=Phenylpropanolamie    -   PPh₃=Triphenylphosphine    -   P(o-tol)₃ or P(o-tolyl)₃=Tri(o-tolyl)phosphine    -   Rochelle's Salt=Potassium sodium tartrate    -   sec-BuLi=Sec-Butyl Lithium    -   TBAF=Tetra-n-butylammonium fluoride    -   TBDMS=Tert-Butyldimethylsilyl    -   TBDMSCl=Tert-Butyldimethylsilyl chloride    -   t-BuNO₂=Tert-Butylnitrate    -   TEA=Triethylamine    -   TF₂O=Triflic anhydride    -   TFA=Trifluoroacetic acid    -   THF=Tetrahydrofuran    -   THP=Tetrahydropyranyl    -   TLC=Thin Layer Chromatography    -   TMEDA=Tetramethylethylenediamine    -   TMS=Trimethylsilyl    -   Tosyl=p-Toluenesulfonyl    -   TsOH or p-TsOH=Toluene sulfonic acid

For purposes of the present invention, the term “modulated by the GPR120receptor” is used to refer to the condition of being affected by themodulation of the GPR120 receptor, including but not limited to, thestate of being mediated by the GPR120 receptor.

As used herein, unless otherwise noted, the term “disorder modulated bythe GPR120 receptor” shall mean any disease, disorder or conditioncharacterized in that at least one of its characteristic symptoms isalleviated or eliminated upon treatment with a GPR120 receptor agonist.Suitably examples include, but are not limited to obesity, obesityrelated disorders, impaired oral glucose tolerance, insulin resistance,Type II diabetes mellitus, metabolic syndrome, metabolic syndrome X,dyslipidemia, elevated LDL, elevated triglycerides, obesity inducedinflammation, osteoporosis and obesity related cardiovascular disorders;preferably, obesity, insulin resistance, Type II diabetes mellitus,dyslipidemia or metabolic syndrome X; more preferably, Type II diabetesmellitus or dyslipidemia.

As used herein unless otherwise noted, the term “obesity relatedcardiovascular disorders” shall mean any cardiovascular disease,disorder or condition in which obesity or diabetes (preferably, Type IIDiabetes) has a role in the initiation or exacerbation of said disorderor condition. Suitable examples include but are not limited tohypertension, atherosclerosis and cardiac fibrosis.

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications (including, to reduce the frequency or severity of one ormore symptoms), or eliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) the delay or avoidance of the development of additionalsymptoms; and/or (b) delay or avoidance of the development of thedisorder or condition along a known development pathway.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need of thereof (i.e.a subject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. A subject in need thereof may additionally be a subject(preferably a mammal, more preferably a human) who has not exhibited anysymptoms of the disorder, disease or condition to be prevented, but whohas been deemed by a physician, clinician or other medical profession tobe at risk of developing said disorder, disease or condition. Forexample, the subject may be deemed at risk of developing a disorder,disease or condition (and therefore in need of prevention or preventivetreatment) as a consequence of the subject's medical history, including,but not limited to, family history, pre-disposition, co-existing(comorbid) disorders or conditions, genetic testing, and the like.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g. base,solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems.

To provide a more concise description, some of the quantitativeexpressions yieldn herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity yieldn herein is meant to refer to the actual yieldnvalue, and it is also meant to refer to the approximation to such yieldnvalue that would reasonably be inferred based on the ordinary skill inthe art, including approximations due to the experimental and/ormeasurement conditions for such yieldn value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any amountor range therein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescriptions which follows herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter. One skilled in the art will further recognizethat wherein a reaction step of the present invention may be carried outin a variety of solvents or solvent systems, said reaction step may alsobe carried out in a mixture of the suitable solvents or solvent systems.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, andthe like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” shall mean a group which may be attached to a oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable oxygen protectinggroups include, but are not limited to, acetyl, benzoyl,t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

Where the processes for the preparation of the compounds according tothe invention yield rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determinepercent enantiomeric excess (% ee). The enantiomeric excess may becalculated as follows

[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixturesuch that Rmoles+Smoles=1. The enantiomeric excess may alternatively becalculated from the specific rotations of the desired enantiomer and theprepared mixture as follows:

ee=([α−obs]/[α−max])×100.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Representative bases which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

General Synthetic Methods

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1, below.

Accordingly, a suitably substituted compound of formula (II), a compoundprepared by known methods or prepared as described hereinafter, isreacted with a suitably substituted compound of formula (III), whereinLG^(A) is a suitably selected leaving group such as OH, and the like,and wherein A¹ is a suitably selected C₁₋₄alkyl, such as methyl, ethyl,t-butyl, and the like, a known compound or compound prepared by knownmethods, in the presence of a suitably selected coupling system such asDEAD/PPh₃, ADDP/Bu₃P, DIAD/PPh₃, and the like; in a suitably selectedorganic solvent such as THF, 1,4-dioxane, CH₂Cl₂, toluene and the like;to yield the corresponding compound of formula (IV).

Alternatively, a suitably substituted compound of formula (II), acompound prepared by known methods or prepared as described hereinafter,is reacted with compounds off formula (III), wherein LG^(A) is asuitably selected leaving group such as F, Cl, Br, mesyl, and the like,a known compound or compound prepared by known methods; in the presenceof a suitably selected base such as NaH, and the like; in a suitablyselected solvent such as DMF, DMSO, NMP, and the like; to yield thecorresponding compound of formula (IV).

One skilled in the art will recognize that compounds of formula (IV) mayalternatively be prepared by reacting a suitably substituted compound offormula (V)

wherein LG^(B) is a suitably selected leaving group such as Cl, Br, I,mesyl, tosyl, and the like, a known compound or compound prepared byknown methods, with a suitably substituted compound of formula (III),wherein LG^(A) is a suitably selected leaving group such as OH, and thelike, a known compound or compound prepared by known methods; in thepresence of a suitably selected base such as potassium carbonate, cesiumcarbonate, TEA, DIEA, and the like; in a suitably selected solvent suchas DMF, THF, DCM, and the like; to yield the corresponding compound offormula (IV).

The compound of formula (IV) is reacted with a suitably selected basesuch as NaOH, LiOH, KOH, and the like; or when A¹ is t-butyl with asuitably selected acid such TFA, and the like; to yield thecorresponding compound of formula (Ia), a compound of formula (I)wherein R⁰ is C(O)OH.

Alternatively, the compound of formula (IV) is reacted with a suitablyselected reducing agent such as LAH, DIBAL, and the like; to yield thecorresponding compound of formula (Ib), a compound of formula (I)wherein R⁰ is CH₂OH.

Compounds of formula (II) wherein

and wherein R² is hydrogen, may be prepared according to the processoutlined in Scheme 2, below.

Accordingly, a suitably substituted compound of formula (2a), whereinLG¹ is a suitably selected leaving group such as Br, I, —OSO₂CF₃, andthe like, and wherein A² is hydrogen or a suitably selected C₁₋₄alkoxysuch as methoxy, ethoxy and the like, a known compound or compoundprepared by known methods, is reacted with a suitably substitutedcompound of formula (2b), a known compound or compound prepared by knownmethods; in the presence of a suitably selected coupling agent such asPd(PPh₃)₂Cl₂, Pd(PPh₃)₄, Pd(dppe)Cl₂ and the like; in the presence ofCuI; in the presence of a suitably selected organic base such as TEA,Et₂NH, and the like; in a suitably selected organic solvent such as DMF,TEA, Et₂NH, and the like; to yield the corresponding compound of formula(2c).

One skilled in the art will further recognize in the preparation of thecompounds of formula (2c), the desired R⁴ and/or R⁵ substituent group(s)may alternatively by reacting a suitably substituted compound of formula(2c) wherein R⁴ and/or R⁵ is CH₃O, with a suitably selectedde-methylating agent such as BBr₃, and the like; and the resultingcompound alkylated with for example, chlorodifluoromethane; to yield thecorresponding compound of formula (2c) wherein R⁴ and/or R⁵ is —OCF₂H;or reacting a suitably substituted compound of formula (2c) wherein R⁴and/or R⁵ is CH₃O—, with bromoethane; to yield the correspondingcompound of formula (2c) wherein R⁴ and/or R⁵ is —OCH₂CH₃; or reacting asuitably substituted compound of formula (2c) wherein R⁴ and/or R⁵ isCH₃O, with for example, 1-bromo-2-methoxyethane; to yield thecorresponding compound of formula (2c) wherein R⁴ and/or R⁵ is—OCH₂CH₂OCH₃; or by reacting a suitably substituted compound of formula(2c) wherein R⁴ and/or R⁵ is CH₃O, with for example, trifluoromethyltrifluoromethanesulfonate; to yield the corresponding compound offormula (2c) wherein R⁴ and/or R⁵ is —OCH₂CF₃; or reacting a suitablysubstituted compound of formula (2c) wherein R⁴ and/or R⁵ is CH₃O, withfor example, 2-bromopropane; to yield the corresponding compound offormula (2c) wherein R⁴ and/or R⁵ is —OCH(CH₃)₂; or reacting a suitablysubstituted compound of formula (2c) wherein R⁴ and/or R⁵ is CH₃O, withfor example, 1-bromo-2-methylpropane; to yield the correspondingcompound of formula (2c) wherein R⁴ and/or R⁵ is —OCH₂CH(CH₃)₂; or byreacting a suitably substituted compound of formula (2c) wherein R⁴and/or R⁵ is CH₃O, with for example, 2-(trimethysilyl)phenyl triflate;to yield the corresponding compound of formula (2c) wherein R⁴ and/or R⁵is —O-phenyl.

Alternatively, a suitably substituted compound of formula (2c) whereinR⁴ and/or R⁵ is CH₃O is reacted with a suitably selected demethylatedagent such as for example BBr₃ and the resulting product reacted withfor example, triflic anhydride; and the resulting product reacted with asuitably substituted boronic acid, under Suzuki coupling conditions(e.g. in the presence of a suitably selected catalyst such as Pd(Ph₃)₄,and the like; in the presence of a suitably selected base such as K₃PO₄,and the like; in a suitably selected solvent such as THF, and the like;to yield the corresponding compound of formula (2c) wherein R⁴ and/or R⁵is CH₃.

Alternatively, a suitably substituted compound of formula (2c) whereinR⁴ and/or R⁵ is CH₃O s reacted with a suitably selected demethylatedagent such as for example BBr₃; and the resulting product reacted withfor example, triflic anhydride; and the resulting product reacted withfor example diethylzinc, in the presence of a suitably selected catalystsuch as Pd(dppf)Cl₂, and the like; in a suitably selected solvent suchas THF, and the like; to yield the corresponding compound of formula(2c) wherein R⁴ and/or R⁵ is CH₂CH₃;

Alternatively, a suitably substituted compound of formula (2c) whereinR⁴ and/or R⁵ is Cl may be reacted with for example, LiAlH₄, and thelike; in a suitably selected solvent such as THF, and the like; to yieldthe corresponding compound of formula (2c) wherein R⁴ and/or R⁵ is H.

Alternatively, a suitably substituted compound of formula (2c) whereinR⁴ and/or R⁵ is iodo may be reacted with for example a suitablysubstituted propy-1-nyl such as 3-(methylsulfanyl)prop-1-yne, in thepresence of CuI, in the presence of a suitably selected catalyst such asPd(PPh₃)₂Cl₂, and the like; in the presence of a suitably selected basesuch as TEA, and the like; in a suitably selected solvent such asacetonitrile, DMF, and the like; at a temperature in the range of fromabout 70° C. to about 90° C.; to yield the corresponding compound offormula (2c) wherein R⁴ and/or R⁵ is CH₃SCH₂CC—.

The compound of formula (2c) is reacted to yield the correspondingcompound of formula (IIa). More particularly, wherein A² is hydrogen,the compound of formula of formula (2c) is reacted with a suitablyselected reducing agent such as NaBH₄, LAH, and the like; in a suitablyselected organic solvent such as THF, MeOH, toluene, and the like; toyield the corresponding compound of formula (IIa). Alternatively,wherein A² is a suitably selected C₁₋₄alkoxy, the compound of formula(2c) is reacted with a suitably selected reducing agent such as DIBAL,LAH, LiBH₄, and the like; in a suitably selected organic solvent such asTHF, toluene, CH₂Cl₂, and the like; at a suitable temperature (asdetermined by the choice of reducing agent and readily determined by oneskilled in the art); to yield the corresponding compound of formula(IIa).

Compounds of formula (II) wherein

and wherein for example, R¹ is methyl and R² is hydrogen, may beprepared according to the process outlined in Scheme 3, below.

Accordingly, a suitably substituted compound of formula (3a), a knowncompound or compound prepared by known methods, is reacted withalkynylbromide, a known compound; in the presence of a suitably selectedinorganic base such as K₂CO₃, Cs₂CO₃, NaH, and the like; in a suitablyselected organic solvent such as DMF, THF, CH₃CN, and the like; to yieldthe corresponding compound of formula (3b).

The compound of formula (3b) is refluxed (at about 217° C.) inN,N-diethylaniline, in the presence of catalytic amounts of CsF to yieldthe corresponding compound of formula (3c).

The compound of formula (3c) is reacted with a suitably selectedreducing agent such as DIBAL, LAH, LiBH₄and the like; in a suitablyselected organic solvent such as THF, toluene, CH₂Cl₂, and the like; toyield the corresponding compound of formula (IIb).

One skilled in the art will recognize that compounds of formula (I)wherein

and wherein R¹ is other than methyl and/or wherein R² is other thanhydrogen, may be similarly prepared according to the process outlined inScheme 3 above by substituting a suitably substituted compound offormula Br—CC(R²) for the alkynyl bromide.

Compounds of formula (II) wherein

and wherein R¹ is methyl and wherein R² is hydrogen, may be preparedaccording to the process outlined in Scheme 4, below.

Accordingly, a suitably substituted compound of formula (4a), a knowncompound or compound prepared by known methods, is reacted with ethyl2-bromopropanoate, a known compound; in the presence of a suitablyselected base such as K₂CO₃, Cs₂CO₃, NaH, DIPEA and the like; in asuitably selected organic solvent such as THF, DMF, acetone, CH₃CN, andthe like; to yield the corresponding compound of formula (4b).

The compound of formula (4b) is reacted with a suitably selectedreducing agent such as DIBAL, LAH, LiBH₄ and the like; in a suitablyselected organic solvent such as THF, Et₂O, CH₂Cl₂ and the like; toyield the corresponding compound of formula (4c).

The compound of formula (4c) is mixed with PPA, and heated at 150° C. toyield the corresponding compound of formula (4d).

The compound of formula (4d) is reacted with carbon monoxide; in thepresence of a suitably selected catalyst such as Pd(dppf)Cl₂,Pd(OAc)₂/1,1′-bis(diphenylphosphino)ferrocene, and the like; in methanolat 60° C. for 18 h to yield the corresponding compound of formula (4e).

The compound of formula (4e) is reacted with a suitably selectedreducing agent such as LAH, LiBH₄, DIBAL, and the like; in a suitablyselected organic solvent such as THF, CH₂Cl₂, toluene and the like; toyield the corresponding compound of formula (IIc).

Compounds of formula (II) wherein

and wherein R¹ is methyl and R² is hydrogen may be prepared according tothe process outlined in Scheme 5, below.

Accordingly, a suitably substituted compound of formula (5a), a knowncompound or compound prepared by known methods, is reacted with NaNO₂and HCl_((aq)) to form the diazonium salt which is then reacted withKSC(═S)OCH₂CH₃, a known compound; neat; to yield the correspondingcompound of formula (5b); which is then reacted with a suitably selectedbase such as KOH, NaOH, and the like; to yield the correspondingcompound of formula (5c).

The compound of formula (5c) is reacted with ethyl 2-bromopropanoate, aknown compound; in the presence of a suitably selected base such asK₂CO₃, Cs₂CO₃, NaH, DIPEA, and the like; in a suitably selected organicsolvent such as THF, DMF, acetone, CH₃CN and the like; to yield thecorresponding compound of formula (5d).

The compound of formula (5d) is reacted with a suitably selectedreducing agent such as DIBAL, LiBH₄, LAH, and the like; in a suitablyselected organic solvent such as THF, CH₂Cl₂, toluene, and the like;preferably at a temperature in the range of form about −78° C. to about20° C., for example, at about −78° C. ((as determined by the choice ofreducing agent and readily determined by one skilled in the art); toyield the corresponding compound of formula (5e).

The compound of formula (5e) is mixed with PPA, a known compound, andheated to about 150° C.; to yield the corresponding compound of formula(5f).

The compound of formula (5f) is reacted with carbon monoxide in thepresence of a suitably selected catalyst such as Pd(dppf)Cl₂,Pd(OAc)₂/1,1′-bis(diphenylphosphino)ferrocene, and the like; in thepresence of a suitably selected organic base such as TEA, in a organicsolvent such as methanol at 60° C. for 18 h; to yield the correspondingcompound of formula (5g).

The compound of formula (5g) is reacted with a suitably selectedreducing agent such as DIBAL, LAH, LiBH₄, and the like; in a suitablyselected organic solvent such as THF, CH₂Cl₂, toluene, and the like;preferably at a temperature in the range of from about −78° C. to about30° C., for example, at about −78° C.; to yield the correspondingcompound of formula (IId).

One skilled in the art will recognize that compounds of formula (I)wherein

and wherein R² is hydrogen and wherein R¹ is other than methyl may besimilarly prepared according to the process outlined in Scheme 4 orScheme 5 above by substituting a suitably substituted compound of theformula Br—CH(R¹)—CO₂CH₂CH₃ for the ethyl 2-bromopropanoate.

Compounds of formula (I) wherein

and wherein R¹ is for example, alkyl, halogen substituted alkyl, alkylester, phenyl or benzyl, may be prepared according to the processoutlined in Scheme 6, below.

Accordingly, a suitably substituted compound of formula (6a), a knowncompound or compound prepared by known methods, is reacted with asuitably selected nitrating agent such as HNO₃/H₂SO₄, KNO₃/H₂SO₄, toyield the corresponding compound of formula (6b).

The compound of formula (6b) is reacted with a suitably selectedreducing agent such as Fe, SnCl₂, TiCl₃; in a suitably selected organicsolvent such as AcOH, EtOAc, THF, and the like; to yield thecorresponding compound of formula (6c).

The compound of formula (6c) is reacted with a suitably substitutedcompound of formula (6d), a known compound or compound prepared by knownmethods; in the presence of a suitably selected acid such as pTsOH, andthe like; preferably at a temperature in the range of from about 100° C.to about 120° C., for example at about 100° C., to yield thecorresponding compound of formula (6e).

The compound of formula (6e) is reacted with a suitably selectedreducing agent such as DIBAL, LAH, LiBH₄, and the like; in a suitablyselected organic solvent such as THF, toluene, CH₂Cl₂, and the like;preferably at a temperature in the range of from about −78° C. to about30° C., for example, at about −78° C.; to yield the correspondingcompound of formula (IIe).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 7, below.

Accordingly, a suitably substituted compound of formula (7a), a knowncompound or compound prepared by known methods, is reacted with forexample, BBr₃, in a suitably selected organic solvent such as CH₂Cl₂,and the like, at about room temperature; to yield the correspondingcompound of formula (7b).

The compound of formula (7b) is reacted with a suitably substitutedcompound of formula (7c), a known compound or compound prepared by knownmethods; in the presence of a suitably selected acid such as pTsOH,sulfuric acid, MsOH, and the like; preferably at a temperature in therange of from about 80° C. to about 120° C., for example at about 100°C.; to yield the corresponding compound of formula (7d).

The compound of formula (7d) is reacted with carbon monoxide in thepresence of a suitably selected catalyst such as Pd(dppf)Cl₂,Pd(OAc)₂/1,1′-bis(diphenylphosphino)ferrocene, and the like; in thepresence of suitably selected inorganic base such as K₂CO₃ in DMF at 80°C. for 18 h to yield the corresponding compound of formula (7e).

The compound of formula (7e) is reacted with for example,TMS-diazomethane, a known compound; in a suitably selected solvent suchas methanol, ethanol, and the like; to yield the corresponding compoundof formula (7f).

The compound of formula (7f) is reacted a suitably selected reducingagent such as DIBAL, LAH, LiBH₄, and the like; in a suitably selectedorganic solvent such as THF, CH₂Cl₂, toluene, and the like; preferablyat a temperature in the range of from about −78° C. to about 30° C., forexample, at about −78° C.; to yield the corresponding compound offormula (IIf).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 8, below.

Accordingly, a suitably substituted compound of formula (8a), a knowncompound or compound prepared by known methods, is reacted (to yield thecorresponding ester) with a suitably selected alkylating agent such asdiethyl sulfate, dimethyl sulfate, and the like; in the presence ofsuitably selected inorganic base such as K₂CO₃, Na₂CO₃, Cs₂CO₃, and thelike; in a suitably selected organic solvent such as acetone, CH₃CN, andthe like; preferably at a temperature in the range of from about 20° C.to about 80° C., for example at about 55° C.; to yield the correspondingcompound of formula (8b) wherein A³ is a suitably selected alkyl,preferably C₁₋₄alkyl, such as methyl, ethyl, t-butyl, and the like.Alternatively the compound of formula (8a) is reacted with for example,diazomethane in methanol or reacted with HCl in a suitably selectedalcohol of the formula A³OH, wherein A³ is methyl or ethyl; to yield thecorresponding compound of formula (8b), wherein A³ is the correspondingalkyl.

The compound of formula (8b) is reacted with phenylmethanethiol, a knowncompound or compound prepared by known methods; in the presence ofsuitably selected inorganic base such as K₂CO₃, Cs₂CO₃, and the like; ina suitably selected organic solvent such as DMF, NMP, DMA, and the like;preferably at a temperature of about 90° C.; to yield the correspondingcompound of formula (8c).

The compound of formula (8c) is reacted with a suitably selectedreducing agent such as Fe, SnCl₂, TiCl₂, and the like; in the presenceof a suitably selected solvent such as ethanol, THF, AcOH, and the like;preferably at a temperature in the range of from about 20° C. to about80° C., for example at about 60° C.; to yield the corresponding compoundof formula (8d).

The compound of formula (8d) is reacted with for example, AlCl₃, in asuitably selected solvent such as toluene, benzene, and the like;preferably at an elevated temperature in the range of from about 30° C.to about 80° C., for example at a temperature of about 30° C.; to yieldthe corresponding compound of formula (8e).

The compound of formula (8e) is reacted with a suitably substitutedcompound of formula (8f), a known compound or compound prepared by knownmethods; in a suitably selected solvent such as NMP, DMF, and the like;preferably at an elevated temperature in the range of from about 150° C.to about 170° C., for example at a temperature of about 160° C.; toyield the corresponding compound of formula (8g).

The compound of formula (8g) is reacted with a suitably selectedreducing agent such as LiAlH₄, BH₃.THF and the like; in a suitablyselected organic solvent such as diethyl ether, THF and the like;preferably at a temperature in the range of form about 0° C. to about22° C., for example, at about 0° C.; to yield the corresponding compoundof formula (IIg).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 9, below.

Accordingly, a suitably substituted compound of formula (9a), a knowncompound or compound prepared by known methods, is reacted with NH₄SCNand Br₂, known compounds; in a suitably selected solvent such as aceticacid, and the like; preferably at a temperature in the range of fromabout 0° C. to about room temperature, for example at about 0° C.; toyield the corresponding compound of formula (9b).

The compound of formula (9b) is reacted with a suitably selected nitritesuch as t-BuNO₂, isoamyl nitrite, and the like; in a suitably selectedorganic solvent such as 1,4-dioxane, THF, DMF, and the like; preferablyat a temperature in the range of from about 50° C. to about 80° C., forexample, at about 60° C.; to yield the corresponding compound of formula(9c).

The compound of formula (9c) is reacted with for example, N₂H₄; in asuitably selected solvent such as ethanol, and the like; preferably at atemperature in the range of from about 70° C. to about 100° C., forexample at about 80° C.; to yield the corresponding compound of formula(9d).

The compound of formula (9d) is reacted with a suitably substitutedcompound of formula (9e), a known compound or compound prepared by knownmethods; in a suitably selected solvent such as NMP, and the like;preferably at a temperature in the range of from about 120° C. to about140° C., for example at about 130° C.; to yield the correspondingcompound of formula (9f).

The compound of formula (9f) is reacted with carbon monoxide in thepresence of a suitably selected catalyst such as Pd(dppf)Cl₂,Pd(OAc)₂/1,1′-bis(diphenylphosphino)ferrocene, and the like; in thepresence of a suitably selected inorganic base such as K₂CO₃, Cs₂CO₃,and the like; in a suitably selected solvent such as DMF, DMSO, and thelike; preferably at a temperature in the range of from about roomtemperature to about 100° C., for example at about 80° C.; to yield thecorresponding compound of formula (9g).

The compound of formula (9g) is reacted with a suitably selectedreducing agent such as LAH, DIBAL, and the like; in a suitably selectedorganic solvent such as THF, DCM, toluene, and the like; preferably at atemperature in the range of from about 0° C. to about 22° C., forexample at about 0° C.; to yield the corresponding compound of formula(IIh).

Compounds of formula (I) wherein

and wherein R¹ is for example, methyl, may alternatively be preparedaccording to the process outlined in Scheme 10, below.

Accordingly, a suitably substituted compound of formula (10a), a knowncompound or compound prepared by known methods, is reacted with aceticanhydride in acetic acid at a temperature in the range of from about 80°C. to about 100° C., for example at about 90° C.; to yield thecorresponding compound of formula (10b).

The compound of formula (10b) is reacted with2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide, aknown compound; in a suitably selected organic solvent such as toluene,benzene, and the like; preferably at a temperature in the range of fromabout 80° C. to about 120° C., for example at about 111° C.; to yieldthe corresponding compound of formula (10c).

The compound of formula (10c) is reacted with3,4,7,8-tetramethyl-1,10-phenanthroline, a known compound; in thepresence of CuI; in the presence of Cs₂CO₃; in a suitably selectedorganic solvent such as DME, 1,4-dioxane, and the like; preferably at atemperature in the range of from about 70° C. to about 100° C., forexample at about 81° C.; to yield the corresponding compound of formula(10d).

The compound of formula (10d) is reacted with carbon monoxide in thepresence of a suitably selected catalyst such as Pd(dppf)Cl₂, and thelike; in the presence of a suitably selected base such as TEA, DIPEA,and the like; in a suitably selected alcohol of the formula A⁶OH,wherein A⁶ is C₁₋₄alkyl, preferably methyl or ethyl (i.e. a C₁₋₄alkylalcohol, preferably methanol or ethanol), and the like; preferably at atemperature of about 60° C.; to yield the corresponding compound offormula (10e).

Alternatively, the compound of formula (10d) is reacted with carbonmonoxide in the presence of a suitably selected catalyst such asPd(dppf)Cl₂, Pd(OAc)₂/1,1′-bis(diphenylphosphino)ferrocene, and thelike; in the presence of suitably selected inorganic base such as K₂CO₃,and the like; in a suitably selected solvent such as DMF, and the like;at a temperature of for example, 80° C.; to yield the correspondingcarboxylic acid, a compound of formula (10f)

which compound of formula (10f) is esterified by reacting with forexample, TMS-diazomethane, a known compound; in a suitably selectedsolvent such as methanol, ethanol, and the like; to yield thecorresponding compound of formula (10e) wherein A⁶ is methyl.

The compound of formula (10e) is reacted with a suitably selectedreducing agent such as DIBAL, LAH, LiBH₄, and the like; in a suitablyselected organic solvent such as CH₂Cl₂, THF, toluene, and the like;preferably at a temperature in the range of form about −78° C. to about22° C., for example, at about −78° C.; to yield the correspondingcompound of formula (IIj).

Compounds of formula (I) wherein

and/or

may be prepared as outlined in Scheme 11, below.

Accordingly, a suitably substituted compound of formula (11a), a knowncompound or compound prepared by known methods, is reacted with asuitably selected base such as NaH, phenyl lithium, and the like; in asuitably selected organic solvent such as THF, diethyl ether, and thelike; and then reacted with a suitably selected base such as t-BuLi,n-BuLi, sec-BuLi and the like, and then with with DMF; in a suitablyselected organic solvent such as THF, 1,4-dioxane, and the like; toyield the corresponding compound of formula (11b). Alternatively, thecompound of formula (11a) is reacted with two or more equivalents of forexample, n-BuLi, and DMF in, for example THF, to yield the correspondingcompound (11b).

The compound of formula (11b) is reacted with a suitably selectedcompound of formula (11c), wherein LG³ is a suitably selected leavinggroup such as Br, I, and the like, a known compound or compound preparedby known methods, according to known methods, to yield a mixture of thecorresponding compound of formula (11d) and the compound of formula(11e). For example, wherein R¹ is alkyl, the compound of formula (11b)is reacted with a suitably selected alkylating agent such as CH₃I,EtOtriflate, EtOmesylate, and the like.

The mixture of the compound of formula (11d) and the compound of formula(11e) is reacted with a suitably selected reducing such asLi(Bu^(t)O)₃AlH, NaBH₄, and the like; in a suitably selected organicsolvent such as THF, methanol, and the like; to yield a mixture of thecorresponding compound of formula (IIk) and the compound of formula(IIm).

The mixture of the compound of formula (IIk) and the compound of formula(IIk) is optionally separated according to known methods, for example byreverse phase HPLC.

Compounds of formula (II) wherein

is selected from the group consisting of

and wherein R² is other than hydrogen, may be prepared as described inScheme 12, below.

Accordingly, a suitably substituted compound of formula (12a), whereinQ¹ is selected from the group consisting of O and S, a known compound orcompound prepared by known methods, is reacted with ethane-1,2-diol, aknown compound; in the presence of p-TsOH, MsOH, and the like; in a thepresence of triethyl orthoformate, a known compound; in a suitablyselected solvent such as toluene, triethyl orthoformate, and the like;to yield the corresponding compound of formula (12b).

The compound of formula (12b) is reacted, according to known methods, toyield the corresponding compound of formula (12c) wherein Hal¹ is chloroor bromo. For example, wherein Hal¹ is chloro, the compound of formula(12b) may be reacted with Cl₂, in the presence of acetic acid.Alternatively, wherein Hal¹ is bromo, the compound of formula (12b) maybe reacted with Br₂, in the presence of sodium acetate, and the like; ina solvent such as chloroform, acetic acid, and the like; preferably attemperature in the range of from about 0° C. to about room temperature.

The compound of formula (12c) is reacted with for example HCl in waterat room temperature to yield the corresponding compound of formula(12d).

Alternatively, the compound of formula (12c) is then further optionallyreacted (through one or more steps), according to known methods, toyield the corresponding compound of formula (12e) wherein R^(X) isselected from the group consisting of halogen, C₁₋₄alkyl, C₂₋₄alkenyland C₂₋₄alkynyl. For example, the compound of formula (12c) may bereacted with a suitably selected fluorinated agent, such as CsF, in thepresence of, for example, a palladium2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenylcatalyst (BrettPhos [(COD)Pd(CH₂TMS)₂]), in a solvent such as toluene,to yield the corresponding compound of formula (12e) wherein R² isfluoro. Alternatively, the compound of formula (12c) may be reacted witha suitably selected alkyl iodide such as CH₃I according to knownmethods, to yield the corresponding compound of formula (12e) wherein R²is C₁₋₄alkyl. Alternatively still, the compound of formula (12c) may bereacted with a suitably selected alkenyl-zinc bromide such asCH₂═CH—ZnBr, and the like in the presence of CH₃MgBr, Niacetylacetonate, 4,5-bis(diphenylphoshino)-9,9-dimethylxanthene, in THFat about 50° C. or with a suitably selected alkynyl such as CCH—CH₃, andthe like, in the presence of TEA, C:CuI, C:PdCl₂(PPh₃)₂, in DMF at about80° C.; to yield the corresponding compound of formula (12e) whereinR^(X) is the corresponding C₂₋₄alkenyl or C₂₋₄alkynyl.

The compound of formula of formula (12e) is reacted to yield thecorresponding compound of formula (12d). For example, the compound offormula (12e) is reacted with H⁺ in water at room temperature; to yieldthe corresponding compound of formula (12d). One skilled in the art willrecognize that wherein the compound of formula (12e) R^(X) isC₂₋₄alkenyl or C₂₋₄alkynyl, reacting the compound of formula (12e) withH₂(g) in the presence of a suitably selected catalyst such as Pd/C, andthe like; to yield conversion of the 1,3-dioxolan-2-yl to hydroxymethyl(remove prot by open ring) and reduction of the C₂₋₄alkenyl orC₂₋₄alkynyl to the corresponding C₂₋₄alkyl.

The compound of formula (12d) is reacted with a suitably selectedreducing agent such as Li(Bu^(t)O)₃AlH, NaBH₄, and the like; in asuitably selected solvent such as methanol, THF, and the like; to yieldthe corresponding compound of formula (IIn).

Compounds of formula (II) wherein

is selected from the group consisting of

and wherein R² is other than hydrogen, may be similarly preparedaccording to the procedures as described in Scheme 12 above, byselecting and substituting a suitably substituted compound of formula(12e)

wherein Q¹ is selected from the group consisting of O and S for thecompound of formula (12a) and reacting as described therein.

Compounds of formula (II) wherein

and wherein R² is other than hydrogen may alternatively be preparedaccording to the procedure as described in Scheme 13, below.

Accordingly, a suitably substituted compound of formula (13a), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (13b), a known compound orcompound prepared by known methods; in the presence of a suitablyselected inorganic base such as K₂CO₃, Cs₂CO₃, and the like; in thepresence of a suitably selected catalyst such as KI, and the like; in asuitably selected solvent such as acetone, DMF, acetonitrile, and thelike; preferably at a temperature in the range of from about 60° C. toabout 120° C., for example at about reflux temperature (about 70° C.);to yield the corresponding compound of formula (13c).

The compound of formula (13c) is reacted with a suitably selected acidsuch as H₂SO₄, TFA, camphosulfonic, and the like; neat; preferably at atemperature in the range of from about 22° C. to about 40° C. (forexample at about 30° C.); to yield the corresponding compound of formula(13d).

The compound of formula (13d) is reacted with a suitably selected basesuch as n-BuLi, isopropyl magnesium chloride, and the like; in thepresence of for example, DMF, and the like; in a suitably selectedsolvent such as THF, diethyl ether, and the like; to yield thecorresponding compound of formula (13e).

The compound of formula (13e) is reacted with a suitably selectedreducing agent such as NaBH₄, DIBAL, and the like; in a suitablyselected solvent such as methanol, THF, DCM, and the like; to yield thecorresponding compound of formula (IIp).

Compounds of formula (II) wherein

and wherein R² is other than hydrogen may alternatively be preparedaccording to the procedure as described in Scheme 14, below.

Accordingly, a suitably substituted compound of formula (14a), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (14b), a known compound orcompound prepared by known methods, in the presence of a suitablyselected inorganic base such as K₂CO₃, Cs₂CO₃, and the like; in thepresence of a suitably selected catalyst such as KI, and the like; in asuitably selected solvent such as acetone, DMF, acetonitrile, and thelike; preferably at a temperature in the range of from about 60° C. toabout 120° C., for example at about reflux temperature (about 70° C.);to yield the corresponding compound of formula (14c).

The compound of formula (14c) is reacted with a suitably selected acidsuch as H₂SO₄, TFA, camphosulfonic, and the like; neat; preferably at atemperature in the range of from about 22° C. to about 40° C. (forexample at about 30° C.); to yield the corresponding compound of formula(14d).

The compound of formula (14d) is reacted with a suitably selectedreducing agent such as DIBAL, LiBH₄, and the like; in a suitablyselected solvent such as DCM, methanol, and the like; to yield thecorresponding compound of formula (IIq).

One skilled in the art will recognize that compounds of formula (II)wherein

is selected from the group consisting of

may be similarly prepared according to the procedures as described inScheme 13 and 14 above, by selecting and substituting a suitablysubstituted compound of formula (14e)

for the compound of formula (14b), therein.

Compounds of formula (II) wherein R⁴ and R⁵ are taken together with thecarbon atoms to which they are bound to form

may be prepared according to the procedure as described in Scheme 15,below.

Accordingly, a suitably substituted compound of formula (15a) is reactedwith bromo(methoxy)methane, a known compound; in the presence of asuitably selected base such as NaH, Cs₂CO₃, and the like; in a suitablyselected solvent such as THF, DMF, and the like; to yield thecorresponding compound of formula (15b).

The compound of formula (15b) is reacted with a suitably selected basesuch as n-BuLi, and the like; in the presence of DMF, and the like; in asuitably selected solvent such as THF, diethyl ether, and the like; toyield the corresponding compound of formula (15c).

The compound of formula (15c) is reacted with a suitably selected acidsuch as TFA, HCl, and the like; in a suitably selected solvent such asDCM, diethyl ether, and the like; to yield the corresponding compound offormula (15d).

The compound of formula (15d) is reacted with a suitably selectedbrominating agent such as Br₂, NBS, and the like; in a suitably selectedsolvent such as chloroform, DCM, and the like; to yield thecorresponding compound of formula (15e).

The compound of formula (15e) is reacted with a suitably substitutedcompound of formula (15f), a known compound or compound prepared byknown methods; in the presence of a suitably selected coupling agentsuch as Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄, Pd(dppe)Cl₂, and the like; in thepresence of CuI; in the presence of a suitably selected organic basesuch as TEA, DIPEA, and the like; neat or in a suitably selected solventsuch as DMF, and the like; to yield the corresponding compound offormula (15g).

The compound of formula (15g) is reacted with a suitably selectedreducing agent such as LAH, NaBH₄, and the like; in a suitably selectedsolvent such as THF, methanol, and the like; to yield the correspondingcompound of formula (IIr).

Compounds of formula (II) wherein R⁴ and R⁵ are taken together with thecarbon atoms to which they are bound to form

may be similarly prepared according to the procedure as described inScheme 15 above, by selecting and substituting a suitably substitutedcompound of formula (15h)

for the compound of formula (15b) and reacting as described therein.

Compounds of formula (II) wherein R⁴ and R⁵ are taken together with thecarbon atoms to which they are bound to form

may be prepared according to the procedure as described in Scheme 16,below.

Accordingly, a suitably substituted compound of formula (16a), a knowncompound or compound prepared by known methods, is reacted with asuitably selected oxidizing agent such as H₂O₂, and the like; in asuitably selected solvent such as diethyl ether, THF, DCM, and the like;to yield the corresponding compound of formula (16b).

The compound of formula (16b) is reacted with bromo(methoxy)methane, aknown compound; in the presence of a suitably selected base such as NaH,Cs₂CO₃, and the like; in a suitably selected solvent such as THD, DMF,and the like; to yield the corresponding compound of formula (16c).

The compound of formula (16c) is reacted with a suitably selected basesuch as n-BuLi, and the like; in the presence of for example, DMF, andthe like; in a suitably selected solvent such as THF, diethyl ether, andthe like; to yield the corresponding compound of formula (16d).

The compound of formula (16d) is reacted with a suitably selectedoxidizing agent such as Ag₂O, mCPBA, sodium hypochlorite, and the like;in a suitably selected solvent such as aqueous NaOH, aqueous potassiumhydroxide, and the like; to yield the corresponding compound of formula(16e).

The compound of formula (16e) is reacted with TMS diazomethane, a knowncompound; in a suitably selected solvent such as methanol, ethanol, andthe like; to yield the corresponding compound of formula (16f).

The compound of formula (16f) is reacted with a suitably selected acidsuch as TFA, HCl, and the like; in a suitably selected solvent such asDCM, diethyl ether, THF, and the like; to yield the correspondingcompound of formula (16g).

The compound of formula (16g) is reacted with a suitably selectedbrominating agent such as Br₂, NBS, and the like; in a suitably selectedsolvent such as chloroform, DCM, and the like; to yield thecorresponding compound of formula (16h).

The compound of formula (16h) is reacted with a suitably substitutedcompound of formula (16i), a known compound or compound prepared byknown methods; in the presence of a suitably selected coupling agentsuch as Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄, Pd(dppe)Cl₂, and the like; in thepresence of CuI; in the presence of a suitably selected organic basesuch as DIPEA, TEA, and the like; neat or in a suitably selected solventsuch as DMF, and the like; to yield the corresponding compound offormula (16j).

The compound of formula (16j) is reacted with a suitably selectedreducing agent such as LAH, NaBH₄, and the like; in a suitably selectedsolvent such as THF, methanol, and the like; to yield the correspondingcompound of formula (IIs).

Compounds of formula (II) wherein R⁴ and R⁵ are taken together with thecarbon atoms to which they are bound to form

may be prepared according to the procedure as described in Scheme 17,below.

Accordingly, a suitably substituted compound of formula (17a), a knowncompound or compound prepared by known methods is reacted with asuitably selected brominating agent such as Br₂, NBS, and the like; in asuitably selected solvent such as chloroform, DCM, and the like; toyield the corresponding compound of formula (17b).

The compound of formula (17b) is reacted with a suitably substitutedcompound of formula (17c), a known compound or compound prepared byknown methods; in the presence of a suitably selected coupling agentsuch as Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄, Pd(dppe)Cl₂, and the like; in thepresence of CuI; in the presence of a suitably selected organic basesuch as TEA, DIPEA, and the like; neat or in a suitably selected solventsuch as DMF, and the like; to yield the corresponding compound offormula (17d).

The compound of formula (17d) is reacted with a suitably selected Lewisacid such as BBr₃, and the like; in a suitably selected solvent such asDCM, DCE, and the like; to yield the corresponding compound of formula(17e).

The compound of formula (17e) is reacted with3-chloro-2-methylprop-1-ene, a known compound; in the presence of asuitably selected base such as K₂CO₃, Cs₂CO₃, and the like; in asuitably selected solvent such as DMF, acetone, and the like; to yieldthe corresponding compound of formula (17f).

The compound of formula (17e) is heated to a temperature in the range offrom about 180° C. to about 200° C., for example to about 192° C.; andmaintained at that temperature to effect a rearrangement; to yield thecorresponding compound of formula (17f).

The compound of formula (17f) is reacted with a suitably selectedorganic acid such as aqueous formic acid, acetic acid, TFA, and thelike; neat or in a suitably selected solvent such as DCM, and the like;to yield the corresponding compound of formula (17g).

The compound of formula (17g) is reacted with TMS diazomethane, a knowncompound; in a suitably selected solvent such as methanol, ethanol, andthe like; to yield the corresponding compound of formula (17h).

The compound of formula (17h) is reacted with a suitably selectedreducing agent such as DIBAL, LAH, and the like; in a suitably selectedsolvent such as DCM, THF, and the like; to yield the correspondingcompound of formula (IIt).

Compounds of formula (II) wherein

wherein R² is hydrogen and wherein R¹ is selected from the groupconsisting of —CN, —C(O)O—(C₁₋₄alkyl) and —C(O)—(C₁₋₄alkyl) may beprepared according to the process outlined in Scheme 18. below.

Accordingly, a suitably substituted compound of formula (18a), whereinLG⁴ is a suitably selected group such as CH₃, Br, I, and the like, aknown compound or compound prepared by known methods; is reacted withfor example, hexamethylenetetramine; in the presence of a suitablyselected acid such as TFA, and the like; neat; at a temperature in therange of from about room temperature to about 100° C., for example, atabout 80° C.; to yield the corresponding compound of formula (18b).

The compound of formula (18b) is reacted with a suitably substitutedcompound of formula (18c), wherein LG⁵ is a suitably selected leavinggroup such as Cl, Br, I, OSO₂CF₃, and the like, and wherein R¹ isselected from the group consisting of —CN, —C(O)O—(C₁₋₄alkyl) and—C(O)—(C₁₋₄alkyl), a known compound or compound prepared by knownmethods, in the presence of a suitably selected base such as potassiumcarbonate, Cs₂CO₃ and the like; in a suitably selected organic solventsuch as acetonitrile, acetone, DMF, and the like; to yield thecorresponding compound of formula (18d).

The compound of formula (18d) is reacted to yield the correspondingcompound of formula (IIv), wherein LG^(B) is a suitably selected leavinggroup such as Br, OH, and the like. Wherein LG⁴ is methyl, the compoundof formula (18d) is reacted with a suitably selected brominating agentsuch as NBS, and the like; in the presence of for example AlBN, and thelike; in a suitably selected solvent such as DCM, CCl₄, and the like; atat temperature in the range of from about 50° C. to about 80° C.; toyield the corresponding compound of formula (IIv), wherein LG^(B) is Br.

Alternatively, wherein LG⁴ is bromo or iodo, the compound of formula(18d) is treated with with carbon monoxide; in the presence of asuitably selected catalyst such as Pd(dppf)Cl₂, and the like; in thepresence of a suitably selected base such as TEA, DIPEA, and the like;in a suitably selected alcohol of the formula A⁴OH, wherein A⁴ isselected from the group consisting of C₁₋₄alkyl, preferably methyl orethyl; at for example, about 60° C.; to yield the corresponding ester, acompound of formula (18e)

which is then reacted with a suitably selected reducing agent such asDIBAL, LAH, LiBH₄, and the like; in a suitably selected organic solventsuch as CH₂Cl₂, THF, toluene, and the like; preferably at a temperaturein the range of form about −78° C. to about 22° C., for example, atabout −78° C.; to yield the corresponding compound of formula (IIv)wherein LG^(B) is OH.

Compounds of formula (I) wherein

and wherein R¹ is selected from the group consisting of—(C₁₋₄alkyl)-NR^(A)R^(B), —(C₁₋₄alkyl)-NR^(A)—C(O)—(C₁₋₄alkyl),—(C₁₋₄alkyl)-NR^(A)—SO₂—(C₁₋₄alkyl) may alternatively be preparedaccording to the procedure as described in Scheme 19, below.

Accordingly, a suitably substituted compound of formula (19a), whereinA⁵ is a —(C₁₋₄alkyl)-, and wherein LG^(C) is OH or a suitably selectedC₁₋₄alkoxy such as methoxy, ethoxy and the like, prepared for example,as described in Scheme 2 above, is protected according to known methods,to yield the corresponding compound of formula (19b) wherein PG¹ is thecorresponding oxygen protecting group. For example, the compound offormula (19a) may be reacted with TBDMSCl in THF; to yield thecorresponding compound of formula (19b), wherein PG¹ is TBDMS.

The compound of formula (19b) is reacted with a suitably selectedreducing agent such as LAH, NaBH₄, and the like; in a suitably selectedsolvent such as THF, MeOH, toluene, and the like; to yield thecorresponding compound of formula (19c).

The compound of formula (19c) is reacted with a suitably substitutedcompound of formula (IIIa), as described in Scheme 1 above, for example,in the presence of a suitably selected coupling system such as forexample a mixture of PPh₃ and DEAD, in a suitably selected solvent suchas THF; to yield the corresponding compound of formula (19d).

The compound of formula (19d) is de-protected according to knownmethods, for example, wherein the protecting group is TBDMS, by reactingwith TBAF in THF; to yield the corresponding compound of formula (19e).

The compound of formula (19e) is reacted with for example mesylchloride, in the presence of a suitably selected organic base such asTEA, and the like, in a suitably selected solvent such as DCM, and thelike; to yield the corresponding compound of formula (19f).

The compound of formula (19f) is then reacted in one or more steps,according to known methods, to further functionalize the R¹ substituentgroup. For example, the compound of formula (19f) may be reacted with asuitably substituted amine of the formula NR^(A)R^(B), in the presenceof a suitably selected base such as K₂CO, and the like, in a suitablyselected solvent such as DMF, and the like; to yield the correspondingcompound of formula (19g) wherein R^(N) is NR^(A)R^(B). Alternatively,the compound of formula (19f) may be reacted with NaN₃, in a suitablyselected solvent such as DMF, and the like; and then further reactedwith a suitably selected reducing agent such as hydrogen in the presenceof a suitably selected catalyst such as Pd/C, and the like, in asuitably selected solvent such as methanol, and the like; to yield thecorresponding compound of formula (19g) wherein R^(N) is NH₂.

One skilled in the art will recognize that the compound of formula (19g)wherein R^(N) is NH₂ may be further reacted according to known methodsto functionalize the terminal amine, for example, by reacting with asuitably substituted acid chloride or a suitably substituted sulfonylchloride, to yield the corresponding compound of formula (19g) whereinR^(N) is —NH—C(O)—(C₁₋₄alkyl) or —NH—SO₂—(C₁₋₄alkyl), respectively.

One skilled in the art will further recognize that the compound offormula (19g) corresponds to the compound of formula (IV) as describedin Scheme 1 above, and may be reacted as described in Scheme 1 above, toyield the corresponding compound of formula (Ia) or formula (Ib).

Compounds of formula (I) wherein

and wherein R¹ is for example, —(C₁₋₄alkyl)-CF₂H or —CHCHF may beprepared according to the procedure as described in Scheme 20, below.

Accordingly, a suitably substituted compound of formula (19e), whereinthe hydroxy group is bound to the A⁵ —(C₁₋₄alkyl)- at a terminal carbonatom, prepared for example as described in Scheme 19 above, is reactedwith a suitably selected oxidized agent such as Dess-Martin periodinane(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one), pyridiniumchlorochromate, and the like; in a suitably selected solvent such asTHF, DCM, and the like; to yield the corresponding compound of formula(19h) (wherein -A⁵=O represents the corresponding aldehyde).

The compound of formula (19h) is reacted with a suitably selectedfluorinating reagent such as diethylaminosulfur trifluoride,bis(2-methoxyethyl)aminosulfur trifluoride, and the like; in a suitablyselected solvent such as THF, DCM, and the like; at a temperature in therange of from about 0° C. to about room temperature; yield thecorresponding compound of formula (19i).

One skilled in the art will further recognize that the compound offormula (19i) corresponds to the compound of formula (IV) as describedin Scheme 1 above, and may be reacted as described in Scheme 1 above, toyield the corresponding compound of formula (Ia) or formula (Ib).

Alternatively, wherein the compound of formula (19i) A² is —CH₂—, thecompound of formula (19i) may be reacted with a suitably selected basesuch as sodium methoxide, sodium hydroxide, and the like; in a suitablyselected solvent such as THF, methanol, and the like; at for example,room temperature; to yield the corresponding compound of formula (19j).

One skilled in the art will further recognize that the compound offormula (19j) corresponds to the compound of formula (IV) as describedin Scheme 1 above, and may be reacted as described in Scheme 1 above, toyield the corresponding compound of formula (Ia) or formula (Ib).

Compounds of formula (II) wherein may be prepared according to theprocedure as described in Scheme 21.

Accordingly, a suitably substituted compound of formula (21a), whereinLG² is a suitably selected leaving group such as bromo, iodo, triflateand the like, and wherein LG⁴ is OH (when W is C(R⁹)) or halogen (when Wis N), a known compound or compound prepared by known methods, isreacted with a suitably substituted compound of formula (21b), whereinA¹ is a suitably selected C₁₋₄alkyl, such as methyl, ethyl, t-butyl, andthe like, a known compound or compound prepared by known methods; in thepresence of a suitably selected catalyst such as PdCl₂, Pd(OAc)₂, andthe like; in the presence of a suitably selected ligand such asP(o-tolyl)₃, PPh₃, and the like; in the presence of a suitably selectedbase such as DIPEA, TEA, and the like; in a suitably selected solventsuch as DMF, NMP, and the like; preferably at a temperature in the rangeof from about 110° C. to about 140° C., for example, at about 120° C.;to yield the corresponding compound of formula (21c).

The compound of formula (21c) is reacted with a suitably selectedreducing agent such as H₂ gas; in the presence of a suitably selectedcatalyst such as Pd/C, and the like; in a suitably selected solvent suchas methanol, ethyl acetate, and the like; to yield the correspondingcompound of formula (IIIa).

One skilled in the art will recognize that compounds of formula (III)may alternatively be prepared according to the procedure as described inScheme 19 above, by selecting and substituting a suitably substitutedcompound of formula (21d)

for the compound of formula (21a) and reacting said compound, asdescribed therein; to yield the corresponding compound of formula (21e)

which compound is then reacted with a suitably selected Lewis acid suchas BBr₃, and the like; in a suitably selected solvent such as DCM, DCE,and the like; to yield the corresponding compound of formula (III).

Compounds of formula (III) wherein W is C(R⁹) and wherein R⁶ and R⁷ areas herein defined, for example, wherein R⁶ and R⁷ are taken togetherwith the carbon atoms to which they are bound to form

may be prepared according to the procedure as described in Scheme 22,below.

Accordingly, a suitably substituted compound of formula (22a), a knowncompound or compound prepared by known methods, is reacted withdichloromethylether, a known compound; in the presence of a suitablyselected Lewis acid such as TiCl₄, and the like; in a suitably selectedsolvent such as DCM, DCE, and the like; to yield the correspondingcompound of formula (22b).

The compound of formula (22b) is reacted with ethyl(triphenylphosphoranylidene)acetate, a known compound; in the presenceof a suitably selected base such as NaH, NaHMDS, and the like; in asuitably selected solvent such as THF, DCM, and the like; to yield thecorresponding compound of formula (22c).

The compound of formula (22c) is reacted with a suitably selectedreducing agent such as H₂ gas; in the presence of a suitably selectedcatalyst such as Pd/C, and the like; in a suitably selected solvent suchas methanol, ethyl acetate, and the like; to yield the correspondingcompound of formula (IIIb).

One skilled in the art will further recognize that the R⁴ substituentgroup may alternatively be incorporated into the compound of formula (I)by reacting a suitably substituted compound of formula (IV) wherein R⁴is for example iodo, according to known methods. For example,

(a) a suitably substituted compound of formula (IV) wherein R⁴ is iodomay be reacted with for example methyl2,2-difluoro-2-(fluorosulfonyl)acetate, in the presence of CuI, NMP/DMPat about 100° C., then reacted with a base for example LiOH, in amixture of THF and water; to yield the corresponding compound of formula(IV) wherein R⁴ is CF₃; alternatively,

(b) a suitably substituted compound of formula (IV) wherein R⁴ is iodomay be reacted with for example a suitable substituted amine of theformula HNR^(C)R^(D), a known compound, in the presence of a catalystsuch as Pd(PPh₃)₂Cl₂, in the presence of CO(g), in a solvent such asDMF; then reacted with a base for example LiOH, in a mixture of THF andwater; to yield the corresponding compound of formula (IV) wherein R⁴ isthe corresponding substituted amide (—C(O)—NR^(C)R^(D)); alternatively,

(c) a suitably substituted compound of formula (IV) wherein R⁴ is iodomay be reacted with for example acetic anhydride, in the presence ofPd₂(dba)₃, DIPEA and LiCl, in DMF, at about 150° C. under microwave; toyield the corresponding compound of formula (IV) wherein R⁴ is —C(O)CH₃;which may be further optionally reacted with for example, DAST in[C_(8min)][PF₆], a known compound, overnight at about 55° C.; thenreacted with a base for example LiOH, in a mixture of THF and water; toyield the corresponding compound of formula (IV) wherein R⁴ is—CF₂(CH₃)₂ alternatively

(d) a suitably substituted compound of formula (IV) wherein R⁴ is iodomay be reacted with for example 2-bromo-3,3,3-trifluoroprop-1-ene, aknown compound, in the presence of DIPEA, n-BuLi, ZnCl₂.TMEDA,Pd(PPh₃)₄, at about 80° C., overnight, to yield the correspondingcompound of formula (IV) wherein R⁴ is —CC—CF₃; alternatively,

(e) a suitably substituted compound of formula (IV) wherein R⁴ is iodomay be reacted with for example a fluoro, chloro or TMS substitutedethyne, in the presence of CuI, Pd(PPh₃)₂Cl₂, TEA, in for example,acetonitrile, overnight at about 70° C. to about 90° C.; then reactedwith a base for example LiOH, in a mixture of THF and water; to yieldthe corresponding compound of formula (IV) wherein R⁴ is thecorresponding fluoro, chloro or TMS substituted ethynyl; which may befurther reacted with for example TBAF, in THF at about 30° C., then witha base for example LiOH, in a mixture of THF and water; to yield thecorresponding compound of formula (IV) wherein R⁴ is ethynyl.

One skilled in the art will further recognize that the R⁴ substituentgroup may alternatively be incorporated into the compound of formula (I)by reacting a suitably substituted compound of formula (IV) wherein R⁴is for example CH₃SCH₂CC—, according to known methods. For example,

(a) a suitably substituted compound of formula (IV) wherein R⁴ is forCH₃SCH₂CC— may be reacted with a suitably selected oxidizing agent suchas mCPBA, potassium peroxysulfate, hydrogen peroxide, and the like; in asuitably selected solvent such as DCM, water/methanol, and the like; toyield the corresponding compound of formula (IV) wherein R⁴CH₃SO₂CH₂CC—, alternatively,

(b) a suitably substituted compound of formula (IV) wherein R⁴ isCH₃SCH₂CC— may be reacted with a suitably selected reducing agent suchas hydrogen; in the presence of a suitably selected catalyst such asPd/C, and the like; to yield the corresponding compound of formula (IV)wherein R⁴ is CH₃SCH₂CH₂CH₂—; which compound is then reacted with asuitably selected oxidizing agent such as mCPBA, potassiumperoxysulfate, hydrogen peroxide, and the like; in a suitably selectedsolvent such as DCM, water/methanol, and the like; to yield thecorresponding compound of formula (IV) wherein R⁴ CH₃SO₂CH₂CH₂CH₂—.

One skilled in the art will further recognize that the transformationsdescribed above may alternatively be applied to compounds of formula(IV) wherein R⁵ is iodo, to yield the corresponding compounds of formula(IV), wherein the R⁵ group is functionalized as described.

Pharmaceutical Compositions

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01 mg to about1000 mg or any amount or range therein, and may be given at a dosage offrom about 0.01 mg/kg/day to about 300 mg/kg/day, or any amount or rangetherein, preferably from about 0.1 mg/kg/day to about 100 mg/kg/day, orany amount or range therein, preferably from about 0.5 mg/kg/day toabout 50 mg/kg/day, preferably from about 1.0 mg/kg/day to about 25mg/kg/day, or any amount or range therein. The dosages, however, may bevaried depending upon the requirement of the patients, the severity ofthe condition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from about 0.01 mg to about1,000 mg, or any amount or range therein, of the active ingredient ofthe present invention. The tablets or pills of the novel composition canbe coated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method(s) of treating disorders as described herein may also becarried out using a pharmaceutical composition comprising any of thecompounds as defined herein and a pharmaceutically acceptable carrier.The pharmaceutical composition may contain between about 0.01 mg andabout 1000 mg of the compound, or any amount or range therein;preferably from about 1.0 mg to about 500 mg of the compound, or anyamount or range therein, and may be constituted into any form suitablefor the mode of administration selected. Carriers include necessary andinert pharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixers, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

To prepare a pharmaceutical composition of the present invention, acompound of formula (I) as the active ingredient is intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration (e.g.oral or parenteral). Suitable pharmaceutically acceptable carriers arewell known in the art. Descriptions of some of these pharmaceuticallyacceptable carriers may be found in The Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders, as described herein, is required.

The daily dosage of the products may be varied over a wide range fromabout 0.01 mg to about 1,000 mg per adult human per day, or any amountor range therein. For oral administration, the compositions arepreferably provided in the form of tablets containing, 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. An effective amount of the drugis ordinarily supplied at a dosage level of from about 0.01 mg/kg toabout 300 mg/kg of body weight per day, or any amount or range therein.Preferably, the range is from about 0.1 to about 100.0 mg/kg of bodyweight per day, or any amount or range therein. More preferably, fromabout 0.5 to about 50.0 mg/kg of body weight per day, or any amount orrange therein. More preferably, from about 1.0 to about 25.0 mg/kg ofbody weight per day, or any amount or range therein. The compounds maybe administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a yieldn disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a yieldn disorder, may be completedaccording to methods well known in the clinical and medical arts.

SYNTHESIS EXAMPLES

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 13-{4-[(5-Fluoro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 5-fluoro-2-methylbenzofuran-7-carboxylate

To a mixture of methyl 3-bromo-5-fluoro-2-hydroxybenzoate (6 g, 24.09mmol, prepared as in Example 5 step (b)), PdCl₂(PPh₃)₂ (1.68 g, 2.39mmol), CuI (456 mg, 2.39 mmol), N,N-dimethylformamide (24 mL) andtriethylamine (4.85 g, 47.93 mmol) at −40° C. was introduced prop-1-yne(1.9 g, 47.42 mmol) for 30 min and the resulting mixture stirred at roomtemperature for 1 hr, and overnight at 75° C. The resulting mixture wasdiluted with ethyl acetate (100 mL). The resulting mixture was washedwith water (3×25 mL). The resulting mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(5/95) to yield methyl 5-fluoro-2-methyl-1-benzofuran-7-carboxylate as awhite solid.

b) (5-Fluoro-2-methylbenzofuran-7-yl)methanol

To a solution of methyl 5-fluoro-2-methyl-1-benzofuran-7-carboxylate (2g, 9.61 mmol), in tetrahydrofuran (70 mL) was added LAH (548 mg, 14.44mmol) in portions at 0° C. The resulting solution was stirred for 30 minat 0° C. in a water/ice bath. The reaction was then quenched by theaddition of Na₂SO₄.10H₂O (3 g). The solids were filtered out. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified on a silica gel column with ethyl acetate/petroleum ether(40/60) to yield (5-fluoro-2-methylbenzofuran-7-yl)methanol as yellowoil.

c) (5-Fluoro-2-methylbenzofuran-7-yl)methyl methanesulfonate

Into a 100-mL round-bottom flask was placed(5-fluoro-2-methyl-1-benzofuran-7-yl)methanol (2.8 g, 15.54 mmol),dichloromethane (50 mL) and triethylamine (4.72 g, 46.64 mmol). To theresulting mixture was then added MsCl (4.47 g) dropwise with stirring at0° C. The resulting solution was stirred for 3 h at 0° C. in a water/icebath. The resulting solution was diluted with DCM (100 mL). Theresulting mixture was washed with water (3×30 mL). The resulting mixturewas dried over anhydrous sodium sulfate and concentrated under vacuum.The resulting residue was purified on a silica gel column with ethylacetate/petroleum ether (10/90) to yield(5-fluoro-2-methyl-1-benzofuran-7-yl)methyl methanesulfonate ascolorless oil.

d) Ethyl3-(4-((5-fluoro-2-methylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 50-mL round-bottom flask was placed ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (2.15 g, 9.67 mmol) (preparedas described in U.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011),N,N-dimethylformamide (15 mL), potassium carbonate (4.01 g, 29.01 mmol),and (5-fluoro-2-methyl-1-benzofuran-7-yl)methyl methanesulfonate (2.5 g,9.68 mmol). The resulting solution was stirred overnight at roomtemperature. The resulting solution was diluted with water (15 mL). Theresulting solution was extracted with ethyl acetate (3×20 mL) and theorganic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (5/95) to yieldethyl3-[4-[(5-fluoro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas a white solid.

e)3-{4-[(5-Fluoro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

Into a 150-mL round-bottom flask was placed ethyl3-[4-[(5-fluoro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(3.5 g, 9.10 mmol), tetrahydrofuran (50 mL), water (50 mL) and LiOH (1.1g, 45.93 mmol). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum and thepH of the solution adjusted to 4-5 with 1N HCl. The solids werecollected by filtration. The resulting solid was dried in an oven underreduced pressure to yield3-[4-[(5-fluoro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoicacid as a white solid.

¹H NMR: (300 MHz, CDCl₃): δ: 7.06-7.13 (m, 2H), 7.00 (d, J=8.4 Hz, 1H),6.81(d, J=8.4 Hz, 1H), 6.38 (s, 1H), 5.32 (s, 2H), 2.97 (t, J=7.5 Hz,2H), 2.61 (t, J=7.2 Hz, 2H), 2.47 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H).Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁FO₄, 355.1 (M−H), found355.1.

Example 23-(4-{[5-Fluoro-2-(3-methylbutyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Methyl 5-fluoro-2-isopentylbenzofuran-7-carboxylate

Into a 50-mL sealed tube, was placed methyl3-bromo-5-fluoro-2-hydroxybenzoate (1 g, 4.02 mmol, prepared as inExample 5 step (b)), Pd(PPh₃)₂Cl₂(282 mg, 0.40 mmol), CuI (76 mg, 0.40mmol), N,N-dimethylformamide (8 mL), TEA (814 mg, 8.04 mmol) and5-methylhex-1-yne (758 mg, 7.88 mmol). The resulting solution wasstirred overnight at 75° C. The resulting solution was diluted withethyl acetate (30 mL). The resulting mixture was washed with saturatedbrine (3×30 mL). The resulting mixture was concentrated under vacuum.The resulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1/30) to yield methyl5-fluoro-2-(3-methylbutyl)-1-benzofuran-7-carboxylate as yellow oil.

b) (5-Fluoro-2-isopentylbenzofuran-7-yl)methanol

To a solution of methyl5-fluoro-2-(3-methylbutyl)-1-benzofuran-7-carboxylate (300 mg, 1.14mmol) in tetrahydrofuran (10 mL) was added LAH (129 mg, 3.40 mmol) inseveral batches at 0° C. The resulting solution was stirred for 1 h at15° C. The reaction was then quenched by the addition of sodiumsulfate.10H₂O (2 g). The solids were filtered out. The resulting mixturewas concentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:30-1:10) toyield 200 mg (67%) of[5-fluoro-2-(3-methylbutyl)-1-benzofuran-7-yl]methanol as yellow oil. c)Ethyl3-(4-((5-fluoro-2-isopentylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed[5-fluoro-2-(3-methylbutyl)-1-benzofuran-7-yl]methanol (50 mg, 0.19mmol, 90%), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (70 mg,0.31 mmol) (prepared as described in U.S. Pat. Appl. Publ., 20110313003,22 Dec. 2011), PPh₃ (83 mg, 0.32 mmol), tetrahydrofuran (3 mL) and DEAD(55 mg, 0.32 mmol). The resulting solution was stirred for 3 h at 30° C.The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with PE/EtOAc (40/1) toyield ethyl3-(4-[[5-fluoro-2-(3-methylbutyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoateas yellow oil.

d)3-(4-[[5-Fluoro-2-(3-methylbutyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid

To a solution of ethyl3-(4-[[5-fluoro-2-(3-methylbutyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate(60 mg, 0.14 mmol) in tetrahydrofuran (3 mL) was added a solution ofLiOH (60 mg, 2.51 mmol) in water (3 mL). The resulting solution wasstirred overnight at 30° C. The resulting mixture was concentrated undervacuum. The pH value of the solution was adjusted to pH 5 with hydrogenchloride (2 N). The resulting solution was extracted with ethyl acetate(2×5 mL) of ethyl acetate and the organic layers combined andconcentrated. The resulting residue was purified by RP-C18-HPLC to yield3-(4-[[5-fluoro-2-(3-methylbutyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a white solid.

¹H NMR: (300 MHz, CDCl₃) δ: 7.05-7.11(m, 2H), 6.98(d, J=8.4 Hz, 1H),6.8(d, J=8.4 Hz, 1H), 6.37(s,1H), 5.30(s,2H), 2.95(t, J=8.4 Hz, 2H),2.77(d, J=7.5 Hz, 1H), 2.60 (t, J=8.4 Hz, 2H), 2.25(s, 7H), 1.60-1.68(m,3H), 0.96(d, J=6.0 Hz, 6H). Mass spectrum (ESI, m/z): Calculated forC₂₅H₂₉FO₄, 413 (M+H), found 413.

Example 33-(4-{[5-Fluoro-2-(2-methoxyethyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Methyl 5-fluoro-2-(2-hydroxyethyl)benzofuran-7-carboxylate

Into a 30-mL sealed tube purged and maintained with an inert atmosphereof nitrogen was placed methyl 3-bromo-5-fluoro-2-hydroxybenzoate (1.24g, 4.98 mmol, prepared as described in Example 5, step (b)),but-3-yn-1-ol (700 mg, 9.99 mmol), Pd(PPh₃)₂Cl₂ (350 mg, 0.50 mmol), CuI(95 mg, 0.50 mmol), triethylamine (1.01 g, 9.98 mmol) andN,N-dimethylformamide (5 mL). The resulting solution was stirred for 21h at 75° C. The reaction was then quenched by the addition of water. Theresulting solution was extracted with ethyl acetate (3×10 mL) and theorganic layers combined and concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (21/79). The collected fractions were combined and concentratedunder vacuum to yield methyl5-fluoro-2-(2-hydroxyethyl)-1-benzofuran-7-carboxylate as a yellowsolid. Mass spectrum (ESI, m/z): Calculated for C₁₂H₁₁FO₄, 239 (M+H),found 239.

b) Methyl 5-fluoro-2-(2-methoxyethyl)benzofuran-7-carboxylate

Into a 50-mL 3-necked round-bottom flask was placed methyl5-fluoro-2-(2-hydroxyethyl)-1-benzofuran-7-carboxylate (500 mg, 2.10mmol), N,N-dimethylformamide (10 mL), sodium hydride (150 mg, 3.75 mmol,60%) and iodomethane (540 mg, 3.80 mmol). The resulting solution wasstirred overnight at 30° C. The reaction was then quenched by theaddition of water. The resulting solution was extracted with ethylacetate (3×5 mL) and the organic layers combined. The resulting mixturewas washed with sodium chloride (ac). The resulting residue was driedover anhydrous sodium sulfate. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (10/90). Theresulting solution was decolorized by the addition of active carbon toyield methyl 5-fluoro-2-(2-methoxyethyl)-1-benzofuran-7-carboxylate ascolorless oil. Mass spectrum (ESI, m/z): Calculated for C₁₃H₁₃FO₄, 253(M+H), found 253.

c)3-(4-{[5-Fluoro-2-(2-methoxyethyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting methyl5-fluoro-2-(2-methoxyethyl)benzofuran-7-carboxylate and ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate, according to the proceduresas described in Example 2.

¹H NMR (300 MHz, CDCl₃) δ 7.14-7.07(m, 2H), 6.98(d, J=8.1 Hz, 1H),6.80(d, J=8.4 Hz, 1H), 6.48(s, 1H), 5.30(s, 2H), 3.75(t, J=6.6 Hz, 2H),3.39(s, 3H), 3.05(t, J=6.6 Hz, 2H), 2.95(t, J=6.6 Hz, 2H), 2.61(t, J=8.1Hz, 2H), 2.25(s, 6H). Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₅FO₅, 423.2 (M+Na), found 423.2.

Example 43-{4-[(5-Fluoro-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedures as describedin Example 2 substituting pent-1-yne for 5-methylhex-1-yne in Step (a).

¹H NMR (300 MHz, CDCl₃) δ: 7.06-7.12 (m, 2H), 6.98 (d, J=8.4 Hz, 1H),6.80 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 2.95 (t, J=8.0 Hz,2H), 2.74 (t, J=8.0 Hz, 2H), 2.57-2.63 (m, 2H), 2.25 (s, 6H), 1.17-1.84(m, 2H), 1.10 (t, J=7.4 Hz, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₃H₂₅FO₄, 407.2 (M+Na), found 407.1.

Example 53-(4-{[5-Fluoro-2-(hydroxymethyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Methyl 5-fluoro-2-hydroxybenzoate

Into a 1-L round-bottom flask was placed 5-fluoro-2-hydroxybenzoic acid(20 g, 128.11 mmol), methanol (250 mL) and sulfuric acid (20 mL). Theresulting solution was stirred overnight at 80° C. The resulting mixturewas concentrated under vacuum. The resulting solution was diluted withethyl acetate (300 mL). The resulting mixture was washed with sodiumbicarbonate (3×100 mL). The resulting residue was dried over anhydroussodium sulfate. The resulting residue was purified on a silica gelcolumn with ethyl acetate/petroleum ether (95:5) to yield methyl5-fluoro-2-hydroxybenzoate as a white solid. Mass spectrum (ESI, m/z):Calculated for C₈H₇FO₃, 172 (M+H), found 172.

b) Methyl 3-bromo-5-fluoro-2-hydroxybenzoate

To a solution of methyl 5-fluoro-2-hydroxybenzoate (14 g, 82.29 mmol) inmethanol (400 mL) was added a solution of Br₂ (14.5 g, 90.73 mmol, 1.13equiv) in methanol (200 mL). The resulting solution was stirredovernight at 15° C. The resulting solution was concentrated and purifiedby silica gel column chromatography with PE/EtOAc (95:5) to yield methyl3-bromo-5-fluoro-2-hydroxybenzoate as a light yellow solid. Massspectrum (ESI, m/z): Calculated for C₈H₆BrFO₃, 249 (M+H), found 249.

c) Methyl5-fluoro-2-(((trimethylsilyl)oxy)methyl)benzofuran-7-carboxylate

A mixture of methyl 3-bromo-5-fluoro-2-hydroxybenzoate (1.86 g, 7.47mmol), trimethyl(prop-2-yn-1-yloxy)silane (1.92 g, 14.97 mmol),Pd(PPh₃)₂Cl₂ (52.5 mg, 0.07 mmol), TEA (1.515 g, 14.97 mmol), CuI (142.5mg, 0.75 mmol) and) in N,N-dimethylformamide (7.5 mL) was stirred for 1h at 25° C. and then for 21 hr at 75° C. The resulting mixture wasdiluted with water (7.5 mL). The resulting solution was extracted withethyl acetate (3×15 mL) and the organic layers combined and dried overanhydrous sodium sulfate. The resulting residue was purified on a silicagel column with ethyl acetate/petroleum ether (20:1˜3:1) to yield methyl5-fluoro-2-[[(trimethylsilyl)oxy]methyl]-1-benzofuran-7-carboxylate aslight yellow oil. Mass spectrum (ESI, m/z): Calculated for C₁₄H₁₄FO₄Si,297 (M+H), found 297.

d) Methyl 5-fluoro-2-(hydroxymethyl)benzofuran-7-carboxylate

To a solution of methyl5-methyl-2-[[(trimethylsilyl)oxy]methyl]-1-benzofuran-7-carboxylate(2.96 g, 5.06 mmol, 50%) in tetrahydrofuran (60 mL) was added TBAF (5.24g, 20.04 mmol). The resulting solution was stirred for 30 min at 25° C.The resulting mixture was concentrated under vacuum. The resultingmixture was washed with water (1×100 mL). The resulting solution wasextracted with ethyl acetate (3×100 mL) and the organic layers combined.The resulting mixture was washed with brine (2×50 mL). The resultingresidue was dried over anhydrous sodium sulfate and concentrated. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (20:1˜2:1) to yield methyl2-(hydroxymethyl)-5-methyl-1-benzofuran-7-carboxylate as light yellowoil. Mass spectrum (ESI, m/z): Calculated for C₁₁H₉FO₄, 225 (M+H), found225.

e) Methyl2-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorobenzofuran-7-carboxylate

A mixture of 5-fluoro-2-(hydroxymethyl)-1-benzofuran-7-carboxylate (800mg, 3.57 mmol), TBDMSCl (566.2 mg, 3.75 mmol), dichloromethane (20 mL)and imidazole (243 mg, 3.57 mmol) was stirred overnight at 20° C. Theresulting mixture was washed with water (1×5 mL). The resulting solutionwas extracted with DCM (3×30 mL) and the organic layers combined anddried over anhydrous sodium sulfate. The resulting residue was purifiedon a silica gel column with ethyl acetate/petroleum ether (200:1˜10:1)to yield methyl2-[[(tert-butyldimethylsilyl)oxy]methyl]-5-fluoro-1-benzofuran-7-carboxylateas light yellow oil. Mass spectrum (ESI, m/z): Calculated forC₁₇H₂₃FO₄Si, 339 (M+H), found 339.

f)(2-(((Tert-butyldimethylsilyl)oxy)methyl)-5-fluorobenzofuran-7-yl)methanol

To a solution of methyl2-[[(tert-butyldimethylsilyl)oxy]methyl]-5-fluoro-1-benzofuran-7-carboxylate(700 mg, 2.07 mmol) in tetrahydrofuran (40 mL) was added LiAlH₄ (236.1mg, 6.22 mmol). The resulting solution was stirred for 5 min at 20° C.The reaction was then quenched by the addition of Na₂SO₄.10H₂O (500 mg).The solids were filtered out. The filtrate was purified on a silica gelcolumn with ethyl acetate/petroleum ether (200:1˜5:1) to yield(2-[[(tert-butyldimethylsilyl)oxy]methyl]-5-fluoro-1-benzofuran-7-yl)methanolas light yellow oil. Mass spectrum (ESI, m/z): Calculated forC₁₆H₂₃FO₃Si, 311 (M+H), found 311.

g) Ethyl3-(4-((2-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a solution of(2-[[(tert-butyldimethylsilyl)oxy]methyl]-5-fluoro-1-benzofuran-7-yl)methanol(124 mg, 0.40 mmol) in tetrahydrofuran (2 mL) was added ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (107 mg, 0.48 mmol), DEAD (84mg, 0.48 mmol), and PPh₃ (126 mg, 0.48 mmol). The resulting solution wasstirred overnight at 30° C. The resulting mixture was concentrated undervacuum. The resulting residue was purified on a silica gel column withethyl acetate/petroleum ether (200:1˜50:1) to yield ethyl3-[4-[(2-[[(tert-butyldimethylsilyl)oxy]methyl]-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas colorless oil. Mass spectrum (ESI, m/z): Calculated for C₂₉H₃₉FO₅Si,515 (M+H), found 515.

h) Ethyl3-(4-((5-fluoro-2-(hydroxymethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a solution of ethyl3-[4-[(2-[[(tert-butyldimethylsilyl)oxy]methyl]-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(100 mg, 0.19 mmol) in tetrahydrofuran (5 mL) was added TBAF (105 mg,0.40 mmol). The resulting solution was stirred for 1 h at 20° C. Theresulting mixture was washed with water (1×5 mL). The resulting residuewas dried over anhydrous sodium sulfate. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(20:1˜4:1) to yield ethyl3-(4-[[5-fluoro-2-(hydroxymethyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoateas a white solid. Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₅FO₅,401 (M+H), found 401.

i)3-(4-((5-Fluoro-2-(hydroxymethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

To a solution of ethyl3-(4-[[5-fluoro-2-(hydroxymethyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate(90 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added a solution ofLiOH (90 mg, 3.76 mmol) in water (5 mL). The resulting solution wasstirred for 14 h at 20° C. The resulting mixture was concentrated undervacuum. The pH of the solution was adjusted to pH 6 with hydrogenchloride (2 mol/L). The solids were collected by filtration to yield3-(4-[[5-fluoro-2-(hydroxymethyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a white solid.

¹H NMR (300 MHz, DMSO-d6) δ: 7.38-7.41 (dd, J1=2.7 Hz, J2=2.4 Hz, 1H),7.18-7.12 (dd, J1=2.4 Hz, J2=2.7 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.87(d, J=8.4 Hz, 1H), 6.81 (s, 1H), 5.30 (s, 1H), 4.58 (s, 1H), 2.73-2.80(m, 2H), 2.40 (t, J=7.4 Hz, 2H), 2.16 (s, 3H), 2.13 (s, 3H). Massspectrum (ESI, m/z): Calculated for C₂₁H₂₁FO₅, 395.1 (M+Na), found395.1.

Example 63-(4-{[5-Fluoro-2-(2-hydroxyethyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedures as describedin Example 5 substituting methyl5-fluoro-2-(2-hydroxyethyl)benzofuran-7-carboxylate (prepared asdescribed in Example 3 step (a)) for methyl5-fluoro-2-(hydroxymethyl)-1-benzofuran-7-carboxylate in step (e).

¹H NMR (300 MHz, CDCl₃) δ: 7.18-7.13 (m, 2H), 7.01 (d, J=8.1 Hz, 1H),6.84 (d, J=8.4 Hz, 1H), 6.55 (s, 1H), 5.340 (s, 2H), 4.04 (t, J=6.0 Hz,2H), 3.09 (t, J=6.3 Hz, 2H), 2.98 (t, J=8.4 Hz, 2H), 2.64 (t, J=7.5 Hz,2H), 2.28 (s, 6H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₃FO₅,409 (M+Na), found 409.

Example 73-{4-[(2-Cyclopentyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedures as describedin Example 2 substituting ethynylcyclopentane for 5-methylhex-1-yne instep (a).

¹H NMR (300 MHz, CDCl₃) δ: 7.06-7.11 (m, 2H), 6.98 (d, J=8.1 Hz, 1H),6.81 (d, J=8.4 Hz, 1H), 6.37 (s,1H), 5.30 (s,2H), 3.16-3.24 (m, 1H),2.95 (t, J=8.4 Hz, 2H), 2.60 (t, J=8.4 Hz, 2H), 2.25 (s, 6H), 1.99-2.11(m, 2H), 1.69-1.80 (m, 9H). Mass spectrum (ESI, m/z): Calculated forC₂₅H₂₇FO₄, 433.2 (M+Na), found 433.0.

Example 83-(4-{[2-(Cyclopentylmethyl)-5-fluoro-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedures as describedin Example 2 substituting prop-2-yn-1-ylcyclopentane for5-methylhex-1-yne in step (a).

¹H NMR (300 MHz, CDCl₃) δ: 7.06-7.11 (m, 2H), 6.97 (d, J=8.1 Hz, 1H),6.80 (d, J=8.4 Hz, 1H), 6.36 (s,1H), 5.29 (s,2H), 2.95 (t, J=8.4 Hz,2H), 2.75 (d, J=7.2 Hz, 1H), 2.60 (t, J=8.4 Hz, 2H), 2.25-2.34 (m, 7H),1.79-1.86 (m, 2H), 1.54-1.68 (m,4H), 1.25-1.31 (m, 2H). Mass spectrum(ESI, m/z): Calculated for C₂₆H₂₉FO₄, 447 (M+Na), found 447.

Example 93-{4-[(2-Benzyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedures as describedin Example 2 substituting prop-2-yn-1-ylbenzene for 5-methylhex-1-yne instep (a).

¹H NMR (300 MHz, CDCl₃) δ: 7.25-7.36 (m, 5H), 7.04-7.13 (m, 2H),6.95 (d,J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.34 (s, 2H), 4.11 (s, 2H), 2.94(t, J=7.5 Hz, 2H), 2.59 (t, J=7.5 Hz, 2H), 2.23 (d, J=3.3 Hz, 6H). Massspectrum (ESI, m/z): Calculated for C₂₇H₂₅FO₄, 431 (M−H), found 431.

Example 103-(4-{[5-Fluoro-2-(methoxymethyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedures as describedin Example 2 substituting methoxyethyne for 5-methylhex-1-yne in step(a).

¹H NMR (300 MHz, CDCl₃) δ: 7.42-7.45 (m, 1H), 7.23-7.27 (m, 1H),6.86-6.95 (m, 3H), 5.31 (s, 2H), 4.55 (s, 2H), 2.72-2.80 (m, 3H), 2.50(s, 3H), 2.38-2.43 (m, 1H), 2.16 (s, 3H), 2.12 (s, 3H). Mass spectrum(ESI, m/z): Calculated for C₂₂H₂₃FO₅, 409 (M+Na), found 409.

Example 113-(4-{[5-Fluoro-2-(1-methylethyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedures as describedin Example 2 substituting 3-methylbut-1-yne for 5-methylhex-1-yne instep (a).

¹H NMR (300 MHz, CDCl₃) δ: 7.07-7.11 (m, 2H), 6.98 (d, J=8.4 Hz, 1H),6.81 (d, J=8.4 Hz, 1H), 6.35 (s, 1H), 5.30 (s, 2H), 2.97-3.11 (m, 1H),2.94 (t, J=8.0 Hz, 2H), 2.60 (t, J=8.0 Hz, 2H), 2.25 (s, 3H), 2.24 (s,3H), 1.35 (s, 3H), 1.33 (s, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₃H₂₅FO₄, 407.2 (M+Na), found 407.1.

Example 123-(4-{[5-Fluoro-2-(2-methylpropyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedures as describedin Example 2 substituting 4-methylpent-1-yne for 5-methylhex-1-yne instep (a).

¹H NMR (300 MHz, CDCl₃) δ: 7.07-7.11 (m, 2H), 6.97 (d, J=8.4 Hz, 1H),6.80 (d, J=8.4 Hz, 1H), 6.37 (s, 1H), 5.30 (s, 2H), 2.95 (t, J=8.0 Hz,2H), 2.57-2.64 (m, 2H), 2.25 (s, 6H), 2.00-2.18 (m, 1H), 0.99 (s, 3H),0.97 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₇FO₄, 399(M+Na), found 399.

Example 133-[4-({2-[2-(Acetylamino)ethyl]-5-fluoro-1-benzofuran-7-yl}methoxy)-2,3-dimethylphenyl]propanoicacid

a) Ethyl3-(4-((5-fluoro-2-(2-((methylsulfonyl)oxy)ethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed ethyl3-(4-[[5-fluoro-2-(2-hydroxyethyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate(1.3 g, 3.14 mmol, prepared as described in Example 6), dichloromethane(20 mL), triethylamine (950 mg, 9.39 mmol) and MsCl (715 mg). Theresulting solution was stirred overnight at 20° C. The reaction was thenquenched by the addition of water. The resulting solution was extractedwith ethyl acetate (3×10 mL) and the organic layers combined. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1/20). The collected fractions were combinedand concentrated under vacuum to yield 1 ethyl3-[4-([5-fluoro-2-[2-(methanesulfonyloxy)ethyl]-1-benzofuran-7-yl]methoxy)-2,3-dimethylphenyl]propanoateas colorless oil. Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₉FO₇S,493 (M+H), found 493.

b) Ethyl3-(4-((2-(2-azidoethyl)-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 100-mL round-bottom flask was placed ethyl3-[4-([5-fluoro-2-[2-(methanesulfonyloxy)ethyl]-1-benzofuran-7-yl]methoxy)-2,3-dimethylphenyl]propanoate(1 g, 2.03 mmol), N,N-dimethylformamide (15 mL) and NaN₃ (132 mg, 2.03mmol). The resulting solution was stirred overnight at 60° C. Thereaction was then quenched by the addition of water. The resultingsolution was extracted with ethyl acetate (3×10 mL) and the organiclayers combined and concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(1/2). The collected fractions were combined and concentrated undervacuum to yield ethyl3-(4-[[2-(2-azidoethyl)-5-fluoro-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoateas colorless oil. Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₆FN30₄,440 (M+H), found 440.

c) Ethyl3-(4-((2-(2-aminoethyl)-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a solution of ethyl3-(4-[[2-(2-azidoethyl)-5-fluoro-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate (700 mg, 1.59 mmol) in MeOH (15 mL) was added Palladium oncarbon (700 mg) and hydrogen and the resulting solution was stirredovernight at 20° C. The solids were filtered out. The resulting mixturewas concentrated under vacuum to yield ethyl3-(4-[[2-(2-aminoethyl)-5-fluoro-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoateas colorless oil.

d) Ethyl3-(4-((2-(2-acetamidoethyl)-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 8-mL vial was placed ethyl3-(4-[[2-(2-aminoethyl)-5-fluoro-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate(50 mg, 0.12 mmol), dichloromethane (2 mL), triethylamine (36 mg, 0.36mmol), and acetyl chloride (11 mg, 0.14 mmol). The resulting solutionwas stirred overnight at 20° C. The resulting mixture was concentratedunder vacuum to yield ethyl3-(4-[[2-(2-acetamidoethyl)-5-fluoro-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoateas yellow oil. Mass spectrum (ESI, m/z): Calculated for C₂₆H₃₀FNO₅, 456(M+H), found 456.

e)3-[4-({2-[2-(Acetylamino)ethyl]-5-fluoro-1-benzofuran-7-yl}methoxy)-2,3-dimethylphenyl]propanoicacid

To a solution of ethyl3-(4-[[2-(2-acetamidoethyl)-5-fluoro-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate(40 mg, 0.09 mmol) in 1 mL of THF was added a solution of LiOH (40 mg,1.67 mmol) in water(1 mL). The resulting solution was stirred overnightat 20° C. The resulting mixture was concentrated under vacuum. Theresulting solution was extracted with ethyl acetate (2×1 mL) and theaqueous layers combined. The pH value of the solution was adjusted to pH2 with hydrogen chloride (1 mol/L). The resulting solution was extractedwith ethyl acetate (3×2 mL) and the organic layers combined andconcentrated under vacuum. The resulting residue was purified byRP-C18-HPLC to yield 1.9 mg (5%) of3-(4-[[2-(2-acetamidoethyl)-5-fluoro-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a white solid.

¹H NMR (300 MHz, DMSO) δ 12.06 (s, 1H), 8.03 (s, 1H), 7.36 (d, J=9.9 Hz,1H), 7.19 (d, J=9.9 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz,1H), 6.72 (s, 1H), 5.32 (s, 1H), 3.43-3.37 (m, 2H), 2.94 (t, J=6.9 Hz,2H), 2.80 (t, J=7.5 Hz, 2H), 2.45-2.18 (m, 2H), 2.18 (s, 6H), 1.81 (s,3H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₆FNO₅, 428 (M+H),found 428.

Example 143-{4-[(5-Fluoro-2-{2-[(methylsulfonyl)amino]ethyl}-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoic acid

a) Ethyl 3-(4-((5-fluoro-2-(2-(methylsulfonamido)ethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 8-mL vial was placed ethyl3-(4-[[2-(2-aminoethyl)-5-fluoro-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate(50 mg, 0.12 mmol, prepared as described in Example 13 step(c)),dichloromethane (2 mL), triethylamine (36 mg, 0.36 mmol) andmethanesulfonyl chloride (16 mg, 0.14 mmol). The resulting solution wasstirred overnight at 20° C. The resulting mixture was concentrated undervacuum to yield ethyl3-(4-[[5-fluoro-2-(2-methanesulfonamidoethyl)-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoateas yellow oil. Mass spectrum (ESI, m/z): Calculated for C₂₅H₃₀FNO₆S, 492(M+H), found 492.

b)3-{4-[(5-Fluoro-2-{2-[(methylsulfonyl)amino]ethyl}-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedures as describedin Example 1.

¹H NMR (300 MHz, DMSO) δ: 7.41-7.37 (m, 1H), 7.25-7.18 (m, 1H), 6.98 (d,J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.77 (s, 1H), 5.32 (s, 2H), 3.02(t, J=7.2 Hz, 2H), 2.91 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 2.45-2.40 (m,4H), 2.18-2.09 (m, 6H). Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₆FNO₆S, 464 (M+H), found 464.

Example 153-[4-({2-[2-(Dimethylamino)ethyl]-5-fluoro-1-benzofuran-7-yl}methoxy)-2,3-dimethylphenyl]propanoicacid

a) Ethyl3-(4-((2-(2-(dimethylamino)ethyl)-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 8-mL vial was placed ethyl3-[4-([5-fluoro-2-[2-(methanesulfonyloxy)ethyl]-1-benzofuran-7-yl]methoxy)-2,3-dimethylphenyl]propanoate(100 mg, 0.20 mmol, prepared as described in Example 13), dimethylamine(49 mg, 1.09 mmol), potassium carbonate (84 mg, 0.61 mmol) andN,N-dimethylformamide (2 mL). The resulting solution was stirredovernight at 40° C. The reaction was then quenched by the addition ofwater. The resulting solution was extracted with ethyl acetate (3×1 mL)and the organic layers combined. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1/10). Thecollected fractions were combined and concentrated under vacuum to yieldethyl3-[4-[[2-(2-(dimethylamino)ethyl]-5-fluoro-1-benzofuran-7-yl]methoxy)-2,3-dimethylphenyl]propanoateas colorless oil. Mass spectrum (ESI, m/z): Calculated for C₂₆H₃₂FNO₄,442 (M+H), found 442.

b)3-[4-({2-[2-(Dimethylamino)ethyl]-5-fluoro-1-benzofuran-7-yl}methoxy)-2,3-dimethylphenyl]propanoicacid

The title compound was prepared according to the procedures as describedin Example 1.

¹H NMR (300 MHz, CDCl₃, ppm) δ: 9.62 (s, 1H), 7.45-742 (m, 1H),7.267-7.22 (m, 1H), 6.91 (d, J=8.4 Hz, 2H), 6.91-6.86 (m, 2H), 5.32 (s,2H), 3.53-3.48 (m, 2H), 3.31-3.26 (m, 2H), 2.88 (s, 6H), 2.81 (t, J=8.1Hz, 3H), 2.43 (t, J=7.2 Hz, 3H), 2.18-2.16 (m, 6H). Mass spectrum (ESI,m/z): Calculated for C₂₄H₂₈FNO₄, 414 (M+H), found 464.

Example 163-{4-[(2-tert-Butyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedures as describedin Example 2 substituting 3,3-dimethylbut-1-yne for 5-methylhex-1-yne instep (a).

¹H NMR (300 MHz, CDCl3) δ: 7.09-7.15 (m, 2H), 7.00 (d, J=8.4 Hz, 1H),6.86 (d, J=8.4 Hz, 1H), 6.37 (s,1H), 5.33 (s,2H), 2.97 (t, J=7.5 Hz,1H), 2.62 (t, J=7.5 Hz, 1H), 2.27 (s, 6H), 1.39 (s, 9H). Mass spectrum(ESI, m/z): Calculated for C₂₄H₂₇FO₄, 399 (M+H), found 399 and 416(M+H30).

Example 173-{4-[(5-Ethoxy-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 3-bromo-5-ethoxy-2-hydroxybenzoate

Into a 250-mL round-bottom flask was placed methyl5-ethoxy-2-hydroxybenzoate (5 g, 27.45 mmol), methanol (100 mL) and Br₂(4.83 g, 30.22 mmol). The resulting solution was stirred overnight atroom temperature. The resulting mixture was concentrated under vacuum.The resulting solution was diluted with ethyl acetate (100 mL) andwashed with Na₂SO₃(ac) (3×20 mL). The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith ethyl acetate/petroleum ether (1:5) to yield methyl3-bromo-5-ethoxy-2-hydroxybenzoate as a light yellow solid. Massspectrum (ESI, m/z): Calculated for C₁₀H₁₁BrO₄, 275.0 (M+H), found275.0.

b) Methyl 5-ethoxy-2-ethylbenzofuran-7-carboxylate

The title compound was prepared by reacting but-1-yne and methyl3-bromo-5-ethoxy-2-hydroxybenzoate according to the procedure in Example2 step (a).

c) (5-Ethoxy-2-ethylbenzofuran-7-yl)methyl methanesulfonate

The title compound was prepared by reacting methyl3-bromo-5-ethoxy-2-hydroxybenzoate by LiAlH₄ reduction and mesylationaccording to the procedure in Example 1 step(b).

d) Ethyl3-(4-((5-ethoxy-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 50-mL round-bottom flask was placed(5-ethoxy-2-ethyl-1-benzofuran-7-yl)methyl methanesulfonate (121 mg,0.41 mmol), potassium carbonate (168 mg, 1.22 mmol),N,N-dimethylformamide (10 mL) and ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (90 mg, 0.40 mmol). Theresulting solution was stirred overnight at room temperature. Theresulting solution was diluted with ethyl acetate (100 mL). Theresulting mixture was washed with brine (3×20 mL). The resulting residuewas dried over anhydrous sodium sulfate. The resulting mixture wasconcentrated under vacuum to yield ethyl3-[4-[(5-ethoxy-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas colorless oil. Mass spectrum (ESI, m/z): Calculated for C₂₆H₃₂O₅, 425(M+H), found 425.

e)3-{4-[(5-Ethoxy-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 1.

¹H NMR (300 MHz, CD₃Cl) δ: 6.98 (s, 1H), 6.96 (d, J=3.0 Hz,1H), 6.91 (d,J=2.4 Hz, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.32 (s, 1H), 5.28 (s, 2H),4.03 (q, J=5.4 Hz, 2H), 2.95 (t, J=7.9 Hz, 2H), 2.77 (t, J=8.4 Hz, 2H),2.59 (t, J=8.1 Hz, 2H), 2.24 (s, 6H), 1.41 (t, J=6.9 Hz, 3H), 1.32 (t,J=7.5 Hz,3H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₅O₅, 395(M−H), found 395.

Example 183-(2,3-Dimethyl-4-{[2-propyl-5-(trifluoromethyl)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid

a) 5-iodo-2-propylbenzofuran-7-carbaldehyde

The title compound was prepared by reacting2-hydroxy-3,5-diiodobenzaldehyde and pent-1-yne according to theprocedure in Example 2 step (a).

b) (5-Iodo-2-propylbenzofuran-7-yl)methanol

To a solution of 5-iodo-2-propyl-1-benzofuran-7-carbaldehyde (2.7 g,8.60 mmol) in tetrahydrofuran (40 mL) was added LiBH₄ (570 mg, 25.91mmol). The resulting solution was stirred for 30 min at 0° C. Thereaction was then quenched by the addition of water (5 mL). Theresulting mixture was concentrated under vacuum. The resulting solutionwas extracted with ethyl acetate (3×30 mL) and the organic layerscombined and dried over sodium sulfate. The solids were filtered out.The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with petroleum ether/EtOAc(200:1˜5:1) to yield (5-iodo-2-propyl-1-benzofuran-7-yl)methanol as alight yellow solid.

c) Ethyl3-(4-((5-iodo-2-propylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

The title compound was prepared by reacting5-iodo-2-propyl-1-benzofuran-7-yl)methanol according to the procedure inExample 1.

d) Ethyl3-(2,3-dimethyl-4-((2-propyl-5-(trifluoromethyl)benzofuran-7-yl)methoxy)phenyl)propanoate

A mixture of ethyl3-[4-[(5-iodo-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(150 mg, 0.29 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (443mg, 2.31 mmol) and CuI (438 mg, 2.30 mmol) in NMP/DMF (7/7 mL) wasstirred for 18 h at 100° C. The resulting solution was diluted withwater (15 mL). The resulting solution was extracted with ethyl acetate(3×30 mL) and the organic layers combined and dried over sodium sulfate.The solids were filtered out. The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith PE/EtOAc (200:1˜10:1) to yield ethyl3-(2,3-dimethyl-4-[[2-propyl-5-(trifluoromethyl)-1-benzofuran-7-yl]methoxy]phenyl)propanoateas light yellow oil.

e)3-(2,3-Dimethyl-4-{[2-propyl-5-(trifluoromethyl)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid

The title compound was prepared according to the procedures as describedin Example 1.

¹H NMR (300 MHz, CDCl₃) δ 7.73 (s,1H), 7.60 (s,1H), 6.98-7.01 (d, J=8.4Hz, 1H), 6.82-6.85 (d, J=8.4 Hz,1H), 6.48 (s,1H), 5.33 (s,2H), 2.93-2.98(t, J=7.8 Hz,2H), 2.75-2.80 (t, J=7.5 Hz,2H), 2.58-2.63 (t, J=7.9Hz,2H), 2.24 (s,6H), 1.72-1.85 (m,2H), 0.99-1.04 (t, J=7.4 Hz,3H). Massspectrum (ESI, m/z): Calculated for C₂₄H₂₅F₃O₄, 433 (M−H), found 433.

Example 193-{4-[(5-Ethynyl-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Ethyl3-(2,3-dimethyl-4-((2-propyl-5-((trimethylsilyl)ethynyl)benzofuran-7-yl)methoxy)phenyl)propanoate

A mixture of ethyl3-[4-[(5-iodo-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(150 mg, 0.29 mmol, prepared as described in Example 18),ethynyltrimethylsilane (57 mg, 0.58 mmol), CuI (5.5 mg, 0.03 mmol), TEA(58 mg, 0.57 mmol), Pd(PPh₃)₂Cl₂ (21 mg, 0.10 equiv) inN,N-dimethylformamide (15 mL) was stirred for 18 h at 90° C. Theresulting solution was diluted with water (15 mL). The resultingsolution was extracted with ethyl acetate (3×30 mL) and the organiclayers combined and dried over sodium sulfate. The solids were filteredout. The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with PE/EtOAc (200:1˜10:1)to yield ethyl3-[2,3-dimethyl-4-([2-propyl-5-[2-(trimethylsilyl)ethynyl]-1-benzofuran-7-yl]methoxy)phenyl]propanoateas light yellow oil.

b) Ethyl3-(4-((5-ethynyl-2-propylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a solution of ethyl3-[2,3-dimethyl-4-([2-propyl-5-[2-(trimethylsilyl)ethynyl]-1-benzofuran-7-yl]methoxy)phenyl]propanoate(150 mg, 0.31 mmol) in tetrahydrofuran (10 mL) was added TBAF (0.6 mL,2.00 equiv). The resulting solution was stirred for 1 h at 30° C. Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with water (5 mL). The resulting solution was extracted withethyl acetate (3×15 mL) and the organic layers combined and dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum to yield ethyl3-[4-[(5-ethynyl-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas light yellow oil.

c)3-{4-[(5-Ethynyl-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting ethyl3-(4-((5-ethynyl-2-propylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoateaccording to the procedures in Example 1.

¹H NMR (300 MHz, CDCl₃) δ 7.59 (s,1H), 7.50 (s,1H), 6.97-6.99 (d, J=8.4Hz, 1H), 6.80-6.83 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 5.28 (s, 2H),2.92-3.00 (m, 3H), 2.72-2.77 (t, J=7.5 Hz, 2H), 2.57-2.63 (t, J=8.1 Hz,2H), 2.24 (s, 6H), 1.71-1.83 (m, 2H), 0.98-1.03 (t, J=7.4 Hz, 3H). Massspectrum (ESI, m/z): Calculated for C₂₅H₂₆O₄, 389 (M−H), found 389.

Example 203-{4-[(5-Chloro-2-ethyl-6-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 2-hydroxy-6-methoxybenzoate

A mixture of 2-hydroxy-6-methoxybenzoic acid (20 g, 118.94 mmol),methanol (300 mL) and sulfuric acid (5 mL) was heated to refluxovernight. The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/hexane (1/30) to yield methyl 2-hydroxy-6-methoxybenzoate ascolorless oil.

b) Methyl 3-chloro-6-hydroxy-2-methoxybenzoate

Into a 500-mL round-bottom flask was placed methyl2-hydroxy-6-methoxybenzoate (15 g, 82.34 mmol), CH₃CN (200 mL), NCS(10.9 g, 81.63 mmol) and CF₃COOH (20 mL). The resulting solution wasstirred for 3 h at 25° C. The resulting mixture was concentrated undervacuum. The resulting solution was diluted with ethyl acetate (300 mL).(300 mL) The resulting mixture was washed with brine (300 mL),NaHCO₃(ac) (300 mL) and brine (300 mL). The resulting residue waspurified on a silica gel column with EtOAc/PE (1/30) to yield methyl3-chloro-6-hydroxy-2-methoxybenzoate as colorless oil.

c) Methyl 3-bromo-5-chloro-2-hydroxy-6-methoxybenzoate

Into a 500-mL round-bottom flask was placed methyl3-chloro-6-hydroxy-2-methoxybenzoate (10.7 g, 49.40 mmol), CH₃CN (200mL) and NBS (6.59 g, 3.42 mmol). The resulting solution was stirred for3 h at 75° C. The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (30/1-1/10) to yield methyl3-bromo-5-chloro-2-hydroxy-6-methoxybenzoate as a yellow solid.

d) Methyl 5-chloro-2-ethyl-6-methoxybenzofuran-7-carboxylate

Into a 150-mL sealed tube was placed methyl3-bromo-5-chloro-2-hydroxy-6-methoxybenzoate (10 g, 33.84 mmol),Pd(PPh₃)₂Cl₂ (5.7 g, 8.12 mmol), CuI (772 mg, 4.05 mmol),N,N-dimethylformamide (80 mL), triethylamine (8.1 g, 80.05 mmol), andbut-1-yne (4.3 g, 79.50 mmol). The resulting mixture was stirredovernight at 75° C. The reaction was then quenched by the addition ofwater (100 mL). The resulting solution was extracted with ethyl acetate(3×100 mL) and the organic layers combined. The resulting mixture waswashed with brine (3×200 mL). The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith ethyl acetate/petroleum ether (1/50-1/30) to methyl5-chloro-2-ethyl-6-methoxy-1-benzofuran-7-carboxylate as brown oil.

e) 5-Chloro-2-ethyl-6-hydroxybenzofuran-7-carboxylic acid

To a solution of methyl5-chloro-2-ethyl-6-methoxy-1-benzofuran-7-carboxylate (7 g, 26.05 mmol)in dichloromethane (200 mL) was added BBr₃ (14 mL) at −70° C. Theresulting solution was stirred for 1 h at 25° C. The reaction was thenquenched by the addition of water (300 mL). The resulting solution wasextracted with ethyl acetate (2×200 mL) and the organic layers combined.The resulting mixture was washed with brine (3×300 mL). The resultingresidue was dried over sodium sulfate and concentrated under vacuum toyield 5-chloro-2-ethyl-6-hydroxy-1-benzofuran-7-carboxylic acid as brownoil.

f) Methyl 5-chloro-2-ethyl-6-hydroxybenzofuran-7-carboxylate

Into a 250-mL round bottom flask, was placed5-chloro-2-ethyl-6-hydroxy-1-benzofuran-7-carboxylic acid (4 g, 16.62mmol), methanol (100 mL) and sulfuric acid (5 mL). The resultingsolution was heated to reflux overnight. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1/30-20/1) toyield methyl 5-chloro-2-ethyl-6-hydroxy-1-benzofuran-7-carboxylate as ayellow solid.

d) Methyl5-chloro-2-ethyl-6-(((trifluoromethyl)sulfonyl)oxy)benzofuran-7-carboxylate

To a mixture of methyl5-chloro-2-ethyl-6-hydroxy-1-benzofuran-7-carboxylate (1 g, 3.93 mmol),dichloromethane (20 mL) and triethylamine (1.2 g, 11.86 mmol) was addedTf₂O (2.2 g, 7.80 mmol). The resulting solution was stirred for 3 h at25° C. The reaction was then quenched by the addition of water (20 mL).The resulting solution was extracted with DCM (2×20 mL) and the organiclayers combined and concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(1/30) to yield methyl5-chloro-2-ethyl-6-[(trifluoromethane)sulfonyloxy]-1-benzofuran-7-carboxylateas a yellow solid.

h) Methyl 5-chloro-2-ethyl-6-methylbenzofuran-7-carboxylate

Into a 10-mL sealed tube was placed methyl5-chloro-2-ethyl-6-[(trifluoromethane)sulfonyloxy]-1-benzofuran-7-carboxylate(300 mg, 0.78 mmol), methylboronic acid (186 mg, 3.11 mmol),tetrahydrofuran (5 mL), K₃PO₄ (655 mg, 3.09 mmol), and Pd(dppf)Cl₂ (113mg, 0.15 mmol). The resulting solution was stirred overnight at 75° C.The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1/30-1/10) to yield methyl5-chloro-2-ethyl-6-methyl-1-benzofuran-7-carboxylate as colorless oil.

i) (5-Chloro-2-ethyl-6-methylbenzofuran-7-yl)methanol

To a solution of methyl5-chloro-2-ethyl-6-methyl-1-benzofuran-7-carboxylate (200 mg, 0.79 mmol)in tetrahydrofuran (10 mL) was added LAH (36 mg, 0.95 mmol, 1.20 equiv)in several batches at 0-5° C. The resulting solution was stirred for 1 hat 25° C. The reaction was then quenched by the addition of Na₂SO₄.10H₂O(1 g). The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1/30-1/5) to yield(5-chloro-2-ethyl-6-methyl-1-benzofuran-7-yl)methanol as a yellow solid.

j) Ethyl3-(4-((5-chloro-2-ethyl-6-methylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed(5-chloro-2-ethyl-6-methyl-1-benzofuran-7-yl)methanol (100 mg, 0.45mmol), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (148 mg, 0.67mmol), toluene (5 mL), ADDP (223 mg, 0.89 mmol) and n-Bu₃P (180 mg, 0.89mmol). The resulting solution was stirred overnight at 60° C. Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with diethyl ether (3 mL). The solids were filtered out. Theresulting residue was purified on a silica gel column with PE/EtOAc(30/1).concentrated under vacuum to yield ethyl3-[4-[(5-chloro-2-ethyl-6-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas yellow oil.

k)3-{4-[5-Chloro-2-ethyl-6-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

To a solution of ethyl3-[4-[(5-chloro-2-ethyl-6-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(120 mg, 0.28 mmol,) in tetrahydrofuran (2 mL) was added a solution ofLiOH (120 mg, 5.01 mmol) in water (2 mL). The resulting solution wasstirred overnight at 40° C. The pH was adjusted to pH 5 with hydrogenchloride (2 mol/L). The resulting solution was extracted with ethylacetate (2×5 mL) and the organic layers combined and concentrated undervacuum. The resulting residue was purified by RP-C18-HPLC to yield3-[4-[(5-chloro-2-ethyl-6-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoicacid as a white solid.

¹H NMR (300 MHz, CDCl₃) δ: 7.48 (s,1H), 6.92-7.03 (m, 2H), 6.30(s,1H),5.32 (s,2H), 2.95 (t, J=7.8 Hz, 2H), 2.73-2.81 (m, 2H), 2.60 (t,J=7.2 Hz, 2H), 2.50 (s,3H),2.22 (s,3H), 2.14 (s,2H), 1.315 (t, J=7.8Hz,3H). Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₅ClO₄, 399 (M−H),found 399.

Example 213-{4-[(2-Carbamoyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 5-Fluoro-2-hydroxy-3-methylbenzaldehyde

Into a 1000-mL round-bottom flask was placed 4-fluoro-2-methylphenol(52.5 g, 416.24 mmol), trifluoroacetic acid (320 mL) and methenamine(103 g). The resulting residue was stirred at 100° C. overnight. To thiswas added sulfuric acid (50 mL, 50%) and water (300 mL) and theresulting solution was stirred for 4 h at 20° C. The resulting mixturewas washed with H₂O. The resulting solution was extracted with ethylacetate (3×50 mL) and the organic layers combined. The resulting mixturewas washed with NH₄HCO₃(ac). The resulting residue was dried overanhydrous sodium sulfate and concentrated under vacuum to yield5-fluoro-2-hydroxy-3-methylbenzaldehyde as a yellow solid.

b) Ethyl 5-fluoro-7-methylbenzofuran-2-carboxylate

Into a 100-mL round-bottom flask was placed5-fluoro-2-hydroxy-3-methylbenzaldehyde (3 g, 19.46 mmol), ethyl2-bromoacetate (4 g, 23.95 mmol), potassium carbonate (8.28 g, 59.91mmol) and CH₃CN (40 mL). The resulting solution was stirred for 60 h at70° C. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (8/92). Thecollected fractions were combined and concentrated under vacuum to yieldethyl 5-fluoro-7-methyl-1-benzofuran-2-carboxylate as colorless oil.

c) 5-Fluoro-7-methylbenzofuran-2-carboxylic acid

To a solution of ethyl 5-fluoro-7-methyl-1-benzofuran-2-carboxylate (3.2g, 14.40 mmol) in 20 mL of THF was added a solution of LiOH (3.2 g,133.61 mmol) in water (20 mL). The resulting solution was stirredovernight at 25° C. The resulting mixture was concentrated under vacuum.The pH value of the solution was adjusted to pH 3 with hydrogen chloride(1 mol/L). The solids were collected by filtration. The solid was driedin an oven under reduced pressure to yield5-fluoro-7-methyl-1-benzofuran-2-carboxylic acid as a white solid.

d) 5-Fluoro-7-methylbenzofuran-2-carboxamide

Into a 100-mL round-bottom flask was placed5-fluoro-7-methyl-1-benzofuran-2-carboxylic acid (1 g, 5.15 mmol),tetrahydrofuran (15 mL) and carbonyl diimidazole (920 mg, 5.67 mmol) andthe mixture was stirred for 2 h at room temperature. NH₃(g) wasintroduced and the mixture was stirred for 1 hr. The reaction was thenquenched by the addition of water. The resulting solution was extractedwith ethyl acetate (3×10 mL) and the organic layers combined and driedover anhydrous sodium sulfate and concentrated under vacuum to yield5-fluoro-7-methyl-1-benzofuran-2-carboxamide as yellow oil.

e) 5-Fluoro-7-methylbenzofuran-2-carbonitrile

Into a 50-mL round-bottom flask was placed5-fluoro-7-methyl-1-benzofuran-2-carboxamide (400 mg, 0.52 mmol),N,N-dimethylformamide (10 mL) and trichloro-1,3,5-triazine (2.2 g, 11.93mmol) and the mixture stirred overnight at 25° C. The reaction was thenquenched by the addition of water. The resulting solution was extractedwith ethyl acetate (3×5 mL) and the organic layers combined andconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (10/90). Thecollected fractions were combined and concentrated under vacuum to yield5-fluoro-7-methyl-1-benzofuran-2-carbonitrile as a white solid.

f) 7-(Bromomethyl)-5-fluorobenzofuran-2-carbonitrile

Into a 50-mL round-bottom flask was placed5-fluoro-7-methyl-1-benzofuran-2-carbonitrile (100 mg, 0.57 mmol), CCl₄(5 mL), NBS (111 mg, 0.62 mmol) and AlBN (9 mg, 0.05 mmol). Theresulting solution was stirred for 16 hr at 70° C. The resulting mixturewas concentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (2/98). Thecollected fractions were combined and concentrated under vacuum to yield7-(bromomethyl)-5-fluoro-1-benzofuran-2-carbonitrile as a yellow solid.

g) Ethyl3-(4-((2-cyano-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 8-mL vial was placed7-(bromomethyl)-5-fluoro-1-benzofuran-2-carbonitrile (60 mg, 0.24 mmol),ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (63 mg, 0.28 mmol),potassium carbonate (40 mg, 0.29 mmol) and CH₃CN (2 mL). The resultingsolution was stirred overnight at 60° C. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (10/90). Thecollected fractions were combined and concentrated under vacuum to yieldethyl3-[4-[(2-cyano-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas a white solid.

h)3-{4-[(2-Carbamoyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

Into a 50-mL round-bottom flask was placed ethyl3-[4-[(2-cyano-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(50 mg, 0.13 mmol), LiOH (50 mg, 2.09 mmol), tetrahydrofuran (2 mL) andwater (2 mL). The resulting solution was stirred overnight at 30° C. ThepH value of the solution was adjusted to pH 2 with hydrogen chloride (1mol/L). The resulting solution was extracted with ethyl acetate (3×1 mL)and the organic layers combined and concentrated under vacuum. Theresulting residue was purified by RP-C18-HPLC to yield3-[4-[(2-carbamoyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoicacid as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 12.09v(s, 1H), 8.17 (s, 1H), 7.78 (s, 1H),7.57 (t, J=5.4 Hz, 2H), 7.38 (d, J=9.6 Hz, 1H), 6.98-6.88 (m, 2H), 5.39(s, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H), 2.27 (s, 6H).Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₀FNO₅, 408.1 (M+Na), found408.1.

Example 227-{[4-(2-Carboxyethyl)-2,3-dimethylphenoxy]methyl}-5-fluoro-1-benzofuran-2-carboxylicacid

Into a 50-mL round-bottom flask was placed ethyl3-[4-[(2-cyano-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(50 mg, 0.13 mmol, prepared as described in Example 21), LiOH (50 mg,2.09 mmol), tetrahydrofuran (2 mL), and water (2 mL). The resultingsolution was stirred overnight at 30° C. The pH value of the solutionwas adjusted to pH 2 with hydrogen chloride (1 mol/L). The resultingsolution was extracted with ethyl acetate (3×1 mL) and the organiclayers combined and concentrated under vacuum. The resulting residue waspurified by RP-C18-HPLC to yield7-[4-(2-carboxyethyl)-2,3-dimethylphenoxymethyl]-5-fluoro-1-benzofuran-2-carboxylicacid as a white solid.

¹H NMR (300 MHz, CDCl₃) δ: 7.68 (s, 1H), 7.60-7.56 (m, 1H), 7.45 (d,J=9.6 Hz, 1H), 6.97-6.88 (m, 2H), 5.35 (s, 2H), 2.78 (t, J=7.5 Hz, 2H),2.40 (t, J=7.2 Hz, 2H), 2.26 (s, 6H). Mass spectrum (ESI, m/z):Calculated for C₂₁H₁₉FO₆, 409.1 (M+Na), found 409.1.

Example 233-{4-[(5-Chloro-2-ethyl-6-methoxy-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl5-chloro-2-ethyl-6-methoxybenzofuran-7-carboxylate (prepared asdescribed in Example 20) according to the procedure in Example 1.

¹H NMR (300 MHz, CDCl₃) δ: 7.50 (s,1H), 6.97-7.07 (m, 2H), 6.32(s,1H),5.29 (s,2H), 3.94 (s,3H), 2.98 (t, J=8.4 Hz, 2H), 2.76-2.79 (m,2H), 2.67 (t, J=8.7 Hz, 2H), 2.24 (s,3H), 2.16 (s,3H), 1.31 (t, J=8.2Hz, 3H). Mass spectrum (ESI, m/z): Calculated for O₂₃H₂₅ClO₅, 415 (M−H),found 415.

Example 243-(4-{[5-(Dimethylcarbamoyl)-2-propyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Ethyl3-(4-((5-(dimethylcarbamoyl)-2-propylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a mixture of ethyl3-[4-[(5-iodo-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(150 mg, 0.29 mmol, prepared as described in Example 18), dimethylamine(0.72 mL, 5.00 equiv), Pd(PPh₃)₂Cl₂ (12.2 mg, 0.02 mmol) inN,N-dimethylformamide (5 mL) was added CO(gas). The resulting solutionwas stirred for 18 h at 25-30° C. The resulting solution was dilutedwith water (10 mL). The resulting solution was extracted with ethylacetate (3×10 mL) and the organic layers combined and dried over sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with PE/EtOAc (5/1) to yield ethyl3-(4-[[5-(dimethylcarbamoyl)-2-propyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoateas light yellow oil.

b) Ethyl3-(4-((5-(dimethylcarbamoyl)-2-propylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a mixture ethyl3-(4-[[5-(dimethylcarbamoyl)-2-propyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate(120 mg, 0.26 mmol) in tetrahydrofuran (5 mL) was added a solution ofLiOH (120 mg, 5.01 mmol) in water (5 mL). The resulting solution wasstirred for 18 h at 25° C. The resulting mixture was concentrated undervacuum. The pH was adjusted to pH 6 with hydrogen chloride (2 mol/L).The solids were collected by filtration to yield3-(4-[[5-(dimethylcarbamoyl)-2-propyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 7.52 (s, 1H), 7.36 (s,1H), 6.94-6.97 (d, J=8.4Hz, 1H), 6.78-6.81 (d, J=8.4 Hz,1H), 6.43 (s, 1H), 5.33 (s, 2H),2.91-2.98 (m, 6H), 2.74-2.79 (m, 4H), 2.55-2.60 (t, J=7.8 Hz, 2H), 2.20(s, 6H), 1.75-1.85 (m, 2H), 0.99-1.04 (t, J=7.4 Hz, 3H). Mass spectrum(ESI, m/z): Calculated for C₂₆H₃₁NO₅, 438 (M+H), found 438.

Example 253-{4-[(5-Iodo-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

To a mixture of ethyl3-[4-[(5-iodo-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(50 mg, 0.10 mmol, prepared as described in Example 18) intetrahydrofuran (5 mL) was added a solution of LiOH (50 mg) in water (5mL). The resulting solution was stirred for 18 h at 25-30° C. Theresulting mixture was concentrated under vacuum. The pH value of thesolution was adjusted to pH 6 with hydrogen chloride (2 mol/L). Thesolids were collected by filtration to3-[4-[(5-iodo-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoicacid as a white solid.

¹H NMR (300 MHz, CDCl₃) δ: 7.76 (s, 1H), 7.66 (s, 1H), 6.96-6.99 (d,J=8.4 Hz, 1H), 6.79-6.82 (d, J=8.4 Hz, 1H), 6.34 (s, 1H), 5.25 (s, 2H),2.92-2.98 (t, J=8.0 Hz, 2H), 2.71-2.76 (t, J=7.4 Hz, 2H), 2.58-2.63 (t,J=8.0 Hz, 2H), 2.23 (s,6H), 1.70-1.82 (m, 2H), 0.97-1.03 (t, J=7.4 Hz,3H). Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₅IO₄, 491 (M−H),found 491.

Example 263-{4-[(2-Cyano-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) (E)-Tert-butyl 3-(4-(benzyloxy)-2,3-dimethylphenyl)acrylate

A mixture of 1-(benzyloxy)-4-bromo-2,3-dimethylbenzene (14.4 g, 49.45mmol), butyl prop-2-enoate (31.7 g, 247.33 mmol), PdCl₂ (0.88 g),(tolyl)₃P (3.01 g), DIEA (19.2 g, 148.56 mmol) and N,N-dimethylformamide(200 mL) was stirred overnight at 80° C. The resulting solution wasdiluted with ethyl acetate (800 mL). The resulting mixture was washedwith water (3×200 mL) and brine (1×200 mL). The resulting residue wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1/99) to yield (E)-tert-butyl3-(4-(benzyloxy)-2,3-dimethylphenyl)acrylate as yellow oil.

b) Tert-butyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate

Into a 250-mL round-bottom flask was placed tert-butyl(2E)-3-[4-(benzyloxy)-2,3-dimethylphenyl]prop-2-enoate (10 g, 29.55mmol), methanol (100 mL), palladium on carbon (10 g) and H₂(gas). Theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum to yield tert-butyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate as a white solid.

c) Tert-butyl3-(4-((2-cyano-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

A mixture of 7-(bromomethyl)-5-fluoro-1-benzofuran-2-carbonitrile (20mg, 0.08 mmol, prepared as described in Example 21, step f), tert-butyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (23 mg, 0.09 mmol), potassiumcarbonate (22 mg, 0.16 mmol) and CH₃CN (1 mL) was stirred overnight at60° C. The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (20/80). The collected fractions were combinedand concentrated under vacuum to yield tert-butyl3-[4-[(2-cyano-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas colorless oil.

d)3-{4-[(2-Cyano-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

A mixture of tert-butyl3-[4-[(2-cyano-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(20 mg, 0.05 mmol), trifluoroacetic acid (0.25 mL), and dichloromethane(1 mL) was stirred for 1 h at 30° C. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified byRP-C18-HPLC to yield3-[4-[(2-cyano-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoicacid as a white solid.

¹H NMR (300 MHz, CDCl₃) δ″ 7.46 (s, 2H), 7.31-7.28 (m, 1H), 6.99 (d,J=7.2 Hz, 2H), 6.76 (d, J=7.2 Hz, 1H), 5.34 (s, 2H), 2.96 (t, J=7.5 Hz,2H), 2.60 (t, J=7.2 Hz, 2H), 2.26 (s, 6H). Mass spectrum (ESI, m/z):Calculated for C₂₁H₁₈FNO₄, 366 (M−H), found 366.

Example 273-(4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-5-fluoro-2-propylphenyl)propanoicacid

The title compound was prepared by reacting(2-propyl-5-(trifluoromethoxy)benzofuran-7-yl)methanol (prepared asdescribed in Example 89 step(e)) and ethyl3-(5-fluoro-4-hydroxy-2-propylphenyl)propanoate (prepared as describedin U.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011), according toprocedure in Example 1.

¹H NMR: (300 MHz, CDCl₃, ppm) δ: 7.26 (s, 1H), 7.24-7.29 (m, 1H),6.84-6.93 (m, 2H), 6.41 (s, 1H), 5.38 (s, 2H), 2.78-2.91 (m, 4H),2.58-2.63 (m, 2H), 2.48-2.53 (m, 2H), 1.49-1.59 (m, 2H), 1.34 (t, J=7.5Hz, 3H), 0.918 (t, J=7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₄H₂₄F₄O₅, 467.2 (M−H), found 467.2.

Example 283-[4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-5-fluoro-2-(3-methylbutyl)phenyl]propanoicacid

a) (E)-1-Fluoro-2-methoxy-4-(3-methylbut-1-en-1-yl)benzene

A mixture of isobutyltriphonylphosphonium bromide (19 g, 47.58 mmol),tetrahydrofuran (100 mL), sodium hydride (1.9 g, 79.17 mmol) and4-fluoro-3-methoxybenzaldehyde (5 g, 32.44 mmol) was stirred for 3 h atroom temperature. The reaction was then quenched by the addition ofwater (100 mL). The resulting solution was extracted with ethyl acetate(3×100 mL) and the organic layers combined and dried over anhydroussodium sulfate and concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(1/50-1/30) to yield(E)-1-fluoro-2-methoxy-4-(3-methylbut-1-en-1-yl)benzene as colorlessoil.

b) 1-Fluoro-4-isopentyl-2-methoxybenzene

To a 100-mL round-bottom flask was placed(E)-1-fluoro-2-methoxy-4-(3-methylbut-1-en-1-yl)benzene (3.3 g, 16.99mmol), palladium on carbon (330 mg), methanol (30 mL) and a balloon ofhydrogen. The resulting solution was stirred for 2 h at roomtemperature, filtered and concentrated to yield1-fluoro-2-methoxy-4-(3-methylbutyl)benzene as colorless oil.

c) 5-Fluoro-2-isopentyl-4-methoxybenzaldehyde

A mixture of 1-fluoro-2-methoxy-4-(3-methylbutyl)benzene (2.9 g, 14.78mmol), dichloromethane (40 mL), TiCl₄ (5 g, 26.60 mmol) anddichloro(methoxy)methane (1.69 g, 14.70 mmol) was stirred for 2 h atroom temperature. The reaction was then quenched by the addition of 40mL of water. The resulting solution was extracted with DCM (40 mL) andthe organic layers combined and concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1/50-1/30) to yield5-fluoro-4-methoxy-2-(3-methylbutyl)benzaldehyde as a yellow solid.

d) (E)-ethyl 3-(5-fluoro-2-isopentyl-4-methoxyphenyl)acrylate

A mixture of (carbethoxymethylene)triphenylphosphorane (5.297 g, 15.20mmol), 5-fluoro-4-methoxy-2-(3-methylbutyl)benzaldehyde (3.1 g, 13.82mmol), and toluene (50 mL) was stirred overnight at 90° C. The resultingmixture was concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(1/50-1/30) to yield ethyl(2E)-3-[5-fluoro-4-methoxy-2-(3-methylbutyl)phenyl]prop-2-enoate asyellow oil.

e) Ethyl 3-(5-fluoro-2-isopentyl-4-methoxyphenyl)propanoate

To a mixture of ethyl(2E)-3-[5-fluoro-4-methoxy-2-(3-methylbutyl)phenyl]prop-2-enoate (3.5 g,11.89 mmol), methanol (100 mL) and palladium on carbon (3 g) was added aballoon of hydrogen and the mixture stirred for 2 h at room temperatureto yield ethyl 3-[5-fluoro-4-methoxy-2-(3-methylbutyl)phenyl]propanoateas yellow oil.

f) Ethyl 3-(5-fluoro-4-hydroxy-2-isopentylphenyl)propanoate

To a solution of ethyl3-[5-fluoro-4-methoxy-2-(3-methylbutyl)phenyl]propanoate (3.2 g, 10.80mmol) in dichloromethane (100 mL) was added BBr₃ (8 mL) dropwise withstirring at −40° C. The resulting solution was stirred for 2 h at roomtemperature. The reaction was then quenched by the addition of water(100 mL). The resulting solution was extracted with DCM (2×100 mL) andthe organic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1/50-1/30) toyield ethyl 3-(5-fluoro-4-hydroxy-2-isopentylphenyl)propanoate ascolorless oil.

g)3-[4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-5-fluoro-2-(3-methylbutyl)phenyl]propanoicacid

The title compound was prepared by reacting ethyl3-(5-fluoro-4-hydroxy-2-isopentylphenyl)propanoate according to Example27.

¹H NMR: (300 MHz, CDCl₃, ppm) δ: 7.29 (s, 1H), 7.23 (s, 1H), 6.92-6.82(m, 2H), 6.41 (s, 1H), 5.38 (s, 2H), 2.91-2.77 (m, 4H), 2.63-2.61 (m,2H), 2.58-2.51 (m, 1H), 1.39-1.31 (m, 5H), 0.93-0.90 (m, 6H). Massspectrum (ESI, m/z): Calculated for C₂₆H₂₈F₄O₅, 495 (M−H), found 495.

Example 293-(7-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dihydro-1H-inden-4-yl)propanoicacid

The title compound was prepared by reacting(2-propyl-5-(trifluoromethoxy)benzofuran-7-yl)methanol (prepared asdescribed in Example 89 step(e)) and ethyl3-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate (prepared as describedin U.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011) according to theprocedure in Example 1.

¹H NMR: (300 MHz, CDCl₃, ppm) δ: 7.28-7.24 (m, 2H), 6.95 (d, J=8.4 Hz,1H), 6.76 (d, J=8.4 Hz, 1H), 5.34 (s, 2H), 2.98-2.86 (m, 6H), 2.83-2.77(m, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.15-2.08 (m, 2H), 1.34 (t, J=7.5 Hz,3H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₃F₃O₅, 447 (M−H),found 447.

Example 303-[4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-5-fluoro-2-(2-methylpropyl)phenyl]propanoicacid

a) 1-Fluoro-2-methoxy-4-(2-methylprop-1-en-1-yl)benzene

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed isopropyltriphenylphosphonium iodide(9.6 g, 22.21 mmol), tetrahydrofuran (40 mL) and sodium hydride (900 mg,22.50 mmol, 60%) and the resulting solution was stirred for 1 h at roomtemperature. To the resulting mixture was then added4-fluoro-3-methoxybenzaldehyde (2.3 g, 14.92 mmol) and the mixture wasstirred overnight at room temperature. The reaction was then quenched bythe addition of water (40 mL). The resulting solution was extracted withethyl acetate (3×40 mL) and the organic layers combined and dried overanhydrous sodium sulfate and concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1/50-1/30) to yield1-fluoro-2-methoxy-4-(2-methylprop-1-en-1-yl)benzene as colorless oil

b) Ethyl 3-(5-fluoro-4-hydroxy-2-isobutylphenyl)propanoate

The title compound was prepared according to procedures in Example 28substituting 1-fluoro-2-methoxy-4-(2-methylprop-1-en-1-yl)benzene for(E)-1-fluoro-2-methoxy-4-(3-methylbut-1-en-1-yl)benzene in step (b).

c)3-[4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-5-fluoro-2-(2-methylpropyl)phenyl]propanoicacid

The title compound was prepared by reacting(2-propyl-5-(trifluoromethoxy)benzofuran-7-yl)methanol (prepared asdescribed in Example 89) and ethyl3-(5-fluoro-4-hydroxy-2-isobutylphenyl)propanoate according to theprocedures in Example 1.

¹H NMR: (300 MHz, CDCl₃, ppm) δ: 7.28 (s, 1H), 7.23 (s, 1H), 6.90 (d,J=12.3 Hz, 1H), 6.78 (d, J=12.3 Hz, 1H), 6.41 (s, 1H), 5.38 (s, 2H),2.89-2.78 (m, 4H), 2.62-2.57 (m, 2H), 2.38 (d, J=7.2 Hz, 2H), 1.77-1.68(m, 1H), 1.36-1.25 (m, 3H), 0.85-0.83 (m, 6H). Mass spectrum (ESI, m/z):Calculated for C₂₅H₂₆F₄O₅, 481 (M−H), found 481.

Example 313-{7-[(5-Chloro-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dihydro-1H-inden-4-yl}propanoicacid

The title compound was prepared by reacting(5-chloro-2-ethylbenzofuran-7-yl)methanol (prepared as described inExample 88 step(b)) and ethyl3-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate (prepared as describedin U.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011) according to theprocedure in Example 20 step (j).

¹H NMR: (300 MHz, CDCl₃) δ: 7.43 (d, J=2.1 Hz, 1H),7.32 (d, J=2.1 Hz,1H), 6.96 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 6.36 (s,1H), 5.32(s,2H), 2.78-3.00 (m, 8H), 2.64 (t, J=8.4 Hz, 2H), 2.01-2.16 (m,3H),2.16 (s,3H), 1.34 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₃ClO₄, 397 (M−H), found 397.

Example 323-{4-[(2-Acetyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 3-Bromo-5-fluoro-2-hydroxybenzaldehyde

A mixture of 2-bromo-4-fluorophenol (5 g, 26.18 mmol), trifluoroaceticacid (60 mL), and hexamethylemetetramine (3.68 g, 26.29 mmol) wasstirred overnight at 80° C. The resulting solution was extracted withethyl acetate (2×20 mL) and the organic layers combined. The resultingmixture was washed with H₂O. The resulting mixture was washed withsodium bicarbonate (ac). The resulting residue was dried over anhydroussodium sulfate and concentrated under vacuum to yield3-bromo-5-fluoro-2-hydroxybenzaldehyde as a yellow solid.

b) 1-(7-Bromo-5-fluorobenzofuran-2-yl)ethanone

Into a 100-mL round-bottom flask was placed3-bromo-5-fluoro-2-hydroxybenzaldehyde (2 g, 9.13 mmol),1-chloropropan-2-one (1.1 g, 11.89 mmol), potassium carbonate (2.25 g,16.28 mmol), and N,N-dimethylformamide (20 mL) and the resultingsolution was stirred for 2 h at 80° C. The reaction was then quenched bythe addition of water. The resulting solution was extracted with ethylacetate (2×20 mL) and the organic layers combined. The resulting mixturewas washed with sodium chloride (ac). The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (10/90). Thecollected fractions were combined and concentrated under vacuum to yield1-(7-bromo-5-fluoro-1-benzofuran-2-yl)ethan-1-one as yellow oil.

c) Methyl 2-acetyl-5-fluorobenzofuran-7-carboxylate

To a mixture of 1-(7-bromo-5-fluoro-1-benzofuran-2-yl)ethan-1-one (2.2g, 8.56 mmol), Pd(dppf)₂Cl₂ (1 g, 1.23 mmol), triethylamine (5 g, 49.41mmol) and methanol (30 mL) was introduced CO (g). The resulting solutionwas stirred overnight at 60° C. The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith ethyl acetate/petroleum ether (20/80). The collected fractions werecombined and concentrated under vacuum to yield methyl2-acetyl-5-fluoro-1-benzofuran-7-carboxylate as a yellow solid.

d) Methyl5-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran-7-carboxylate

Into a 100-mL round-bottom flask was placed methyl2-acetyl-5-fluoro-1-benzofuran-7-carboxylate (500 mg, 2.12 mmol),ethane-1,2-diol (5 g, 80.56 mmol), TsOH (40 mg, 0.23 mmol) and toluene(10 mL) and the mixture was stirred overnight at 70° C. The resultingmixture was concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(30/70). The collected fractions were combined and concentrated undervacuum to yield methyl5-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-carboxylate asyellow oil.

e) (5-Fluoro-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran-7-yl)methanol

To a solution of methyl5-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-carboxylate (400mg, 1.43 mmol) in tetrahydrofuran (10 mL) was added LAH (163 mg, 4.30mmol) and the resulting solution was stirred for 2 h at 30° C. Thereaction was then quenched by the addition of sodium sulfate.10H₂O. Thesolids were filtered out. The resulting mixture was concentrated undervacuum to yield[5-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-yl]methanol asyellow oil.

f) 1-(5-Fluoro-7-(hydroxymethyl)benzofuran-2-yl)ethanone

Into a 8-mL vial was placed[5-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-yl]methanol (30mg, 0.12 mmol), acetone (1 mL), and hydrogen chloride (1N) (1 mL). Theresulting solution was stirred for 2 h at 30° C. The resulting solutionwas extracted with ethyl acetate (3×1 mL) and the organic layerscombined and concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(35/65). The collected fractions were combined and concentrated undervacuum to yield1-[5-fluoro-7-(hydroxymethyl)-1-benzofuran-2-yl]ethan-1-one as a whitesolid.

g) (2-Acetyl-5-fluorobenzofuran-7-yl)methyl methanesulfonate

Into a 8-mL vial was placed1-[5-fluoro-7-(hydroxymethyl)-1-benzofuran-2-yl]ethan-1-one (20 mg, 0.10mmol), dichloromethane (1 mL), methanesulfonyl chloride (20 mg, 0.17mmol), and triethylamine (30 mg, 0.30 mmol) and the mixture was stirredovernight at 30° C. The reaction was then quenched by the addition ofwater. The resulting solution was extracted with ethyl acetate (3×1 mL)and the organic layers combined and dried over anhydrous sodium sulfateand concentrated under vacuum to yield(2-acetyl-5-fluoro-1-benzofuran-7-yl)methyl methanesulfonate as yellowoil.

h) Tert-butyl3-(4-((2-acetyl-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

A mixture of (2-acetyl-5-fluoro-1-benzofuran-7-yl)methylmethanesulfonate (30 mg, 0.10 mmol), tert-butyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (28 mg, 0.11 mmol, preparedas described in Example 22), and potassium carbonate (45 mg, 0.33 mmol),in N,N-dimethylformamide (1 mL) was stirred overnight at 30° C. Theresulting solution was diluted with of H₂O. The resulting solution wasextracted with ethyl acetate (2×1 mL) and the organic layers combined.The resulting solution was extracted with of ethyl acetate and theorganic layers combined. The resulting residue was purified bypreparative-TLC with ethyl acetate/petroleum ether (1/5). The resultingsolution was extracted with of ethyl acetate and the organic layerscombined to yield tert-butyl3-[4-[(2-acetyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas yellow oil.

i)3-{4-[(2-Acetyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

A mixture of tert-butyl3-[4-[(2-acetyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(20 mg, 0.05 mmol), dichloromethane (1 mL) and trifluoroacetic acid (0.2mL) was stirred for 3 h at 30° C. The resulting mixture was concentratedand purified by RP-C18-HPLC to yield3-[4-[(2-acetyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoicacid as a white solid.

¹H NMR: (300 MHz, CDCl₃) δ: 7.50 (s, 1H), 7.44-7.43 (m, 1H), 7.32-7.29(m, 2H), 6.95 (d, J=8.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 5.39 (s, 2H),2.98-2.99 (m, 2H), 2.78-2.61 (m, 5H), 2.13-2.17 (m, 6H). Mass spectrum(ESI, m/z): Calculated for C₂₂H₂₁FO₅, 383 (M−H), found 383.

Example 333-(4-{[5-(Difluoromethoxy)-2-ethyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Methyl 3-bromo-2-hydroxy-5-methoxybenzoate

To a solution of methyl 2-hydroxy-5-methoxybenzoate (10 g, 54.89 mmol)in methanol (150 g, 4.68 mol) was added Br₂ (10.4 g, 65.08 mmol) and theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum and diluted with ethylacetate (100 mL) and washed with Na₂S₂O₃ (ac) (3×50 mL). The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1:3) to yield methyl 3-bromo-2-hydroxy-5-methoxybenzoate asyellow oil.

b) Methyl 2-ethyl-5-methoxybenzofuran-7-carboxylate

A mixture of methyl 3-bromo-2-hydroxy-5-methoxybenzoate (10.3 g, 39.45mmol), N,N-dimethylformamide (100 mL), TEA (8.0 g, 79.06 mmol), CuI (750mg, 3.94 mmol), Pd(PPh₃)₂Cl₂ (2.77 g, 3.95 mmol) and but-1-yne (4.28 g,79.13 mmol) was stirred overnight at 80° C. The resulting solution wasdiluted with ethyl acetate (300 mL). The resulting mixture was washedwith brine (3×50 mL). The resulting residue was dried over anhydroussodium sulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:3) to yieldmethyl 2-ethyl-5-methoxy-1-benzofuran-7-carboxylate as yellow oil

c) Methyl 2-ethyl-5-hydroxybenzofuran-7-carboxylate

To a solution of methyl 2-ethyl-5-methoxy-1-benzofuran-7-carboxylate(1.5 g, 6.40 mmol) in dichloromethane (50 mL) was added BBr₃ (3.2 g) at−78° C. The resulting solution was stirred for 30 min at roomtemperature. The reaction was then quenched by the addition of water (15mL). The resulting solution was diluted with DCM (100 mL). The resultingmixture was washed with brine (3×40 mL). The resulting residue was driedover anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1:3) to yield methyl 2-ethyl-5-hydroxy-1-benzofuran-7-carboxylate asyellow oil.

d) Methyl 5-(difluoromethoxy)-2-ethyl-1-benzofuran-7-carboxylate

Into a 25-mL round-bottom flask was placed methyl2-ethyl-5-hydroxy-1-benzofuran-7-carboxylate (280 mg, 1.27 mmol),1,4-dioxane (15 mL), water (0.5 mL), sodium hydroxide (153 mg, 3.83mmol), tetrabutylammonium iodide (469.6 mg, 1.27 mmol), andchlorodifluoromethane (219 mg, 2.53 mmol) and the mixture was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The resulting solution was diluted with ethyl acetate (50mL). The resulting mixture was washed with brine (3×10 mL). Theresulting residue was dried over anhydrous sodium sulfate. The solidswere filtered out. The resulting mixture was concentrated under vacuum.The resulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1:3) to yield methyl5-(difluoromethoxy)-2-ethyl-1-benzofuran-7-carboxylate as colorless oil.

e)3-(4-{[5-(Difluoromethoxy)-2-ethyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting methyl5-(difluoromethoxy)-2-ethyl-1-benzofuran-7-carboxylate and ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (prepared as described inU.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011) according to procedurein Example 1.

¹H NMR: (300 MHz, CD₃Cl) δ: 7.19 (d, J=2.7 Hz, 2H), 6.99 (d, J=8.4 Hz,1H), 6.82 (d, J=10.8 Hz, 1H), 6.49 (t, J=74.4 Hz, 1H), 6.40 (s, 1H),6.32 (s, 1H), 5.31 (s, 2H), 2.96 (t, J=7.8 Hz, 2H), 2.82 (q, J₁=7.5 Hz,J₂=1.2 Hz, 2H), 2.61 (t, J=8.4 Hz, 2H), 2.26 (s, 6H), 1.35 (t, J=7.5 Hz,3H). Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₄F₂O₅, 317 (M−H),found 417.

Example 343-{2,3-Dimethyl-4-[(2-propyl-5-prop-1-yn-1-yl-1-benzofuran-7-yl)methoxy]phenyl}propanoicacid

a) Ethyl3-(2,3-dimethyl-4-((5-(prop-1-yn-1-yl)-2-propylbenzofuran-7-yl)methoxy)phenyl)propanoate

To a mixture of ethyl3-[4-[(5-iodo-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(520 mg, 1.00 mmol, prepared as described in Example 18), CuI (15 mg,0.08 mmol), Pd(PPh₃)₂Cl₂ (54 mg), and triethylamine (1 mL) in MeCN (2mL) was added prop-1-yne (15.4 mg, 0.38 mmol) dropwise with stirring at−78° C. The resulting solution was stirred overnight at 25° C. Theresulting solution was diluted with ethyl acetate (20 mL). The solidswere filtered out. The resulting mixture was concentrated under vacuum.The resulting residue was purified on a silica gel column with ethylacetate/petroleum ether (10/90). The collected fractions were combinedand concentrated under vacuum to yield ethyl3-(2,3-dimethyl-4-[[5-(prop-1-yn-1-yl)-2-propyl-1-benzofuran-7-yl]methoxy]phenyl)propanoateas light yellow oil.

b)3-{2,3-Dimethyl-4-[(2-propyl-5-prop-1-yn-1-yl-1-benzofuran-7-yl)methoxy]phenyl}propanoicacid

The title compound was prepared according to procedure as described inExample 1.

¹H NMR: (300 MHz, CDCl₃) δ: 7.47 (s,1H), 7.39 (s,1H), 6.99 (d, J=8.4 Hz,1H), 6.83 (d, J=8.4 Hz, 1H), 6.35 (s,1H), 5.26 (s,2H), 2.95 (t, J=8.1Hz,2H), 2.73 (t, J=7.2 Hz,2H), 2.59 (t, J=7.5 Hz, 2H), 2.21 (s,6H), 2.05(s,3H), 1.80-1.82 (m,2H), 1.03 (t, J=7.2 Hz,3H), 1.35 (t, J=7.5 Hz, 3H).Mass spectrum (ESI, m/z): Calculated for C₂₆H₂₈O₄, 403 (M−H), found 403.

Example 353-{4-[(5-Chloro-2,6-diethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 5-chloro-2,6-diethylbenzofuran-7-carboxylate

A mixture of methyl5-chloro-2-ethyl-6-[(trifluoromethane)sulfonyloxy]-1-benzofuran-7-carboxylate(200 mg, 0.52 mmol, prepared as described in Example 20 step g),tetrahydrofuran (4 mL), Pd(dppf)Cl₂ (37 mg, 0.05 mmol), LiCl (150 mg,3.57 mmol), and diethylzinc (310 mg, 2.51 mmol) was stirred overnight at60° C. The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1/30-1/20) to yield methyl5-chloro-2,6-diethyl-1-benzofuran-7-carboxylate as yellow oil.

b)3-{4-[(5-Chloro-2,6-diethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl5-chloro-2,6-diethyl-1-benzofuran-7-carboxylate according to procedurein Example 1.

¹H NMR: (300 MHz, CDCl₃) δ: 7.43 (s,1H), 6.85-6.97 (m, 2H), 6.24 (s,1H),5.19 (s,2H), 2.86-2.89 (m, 4H), 2.573-2.68 (m, 4H), 2.15 (s,3H), 2.06(s,3H), 1.14-1.25 (m,6H). Mass spectrum (ESI, m/z): Calculated forC₂₄H₂₇ClO₄, 413 (M−H), found 413.

Example 363-{4-[(5-Chloro-6-ethoxy-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 5-chloro-6-ethoxy-2-ethylbenzofuran-7-carboxylate

Into a 8-mL vial, was placed methyl5-chloro-2-ethyl-6-hydroxy-1-benzofuran-7-carboxylate (100 mg, 0.39mmol, prepared as described in Example 20, step(e)), acetone (2 mL),bromoethane (0.5 mL), Cs₂CO₃ (639 mg, 1.96 mmol). The resulting solutionwas stirred overnight at 60° C. The reaction was then quenched by theaddition of water (5 mL). The resulting solution was extracted withethyl acetate (2×5 mL) and the organic layers combined and concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith P/E (30/1-20/1) to yield methyl5-chloro-6-ethoxy-2-ethyl-1-benzofuran-7-carboxylate as yellow oil.

b)3-{4-[(5-Chloro-6-ethoxy-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl5-chloro-6-ethoxy-2-ethyl-1-benzofuran-7-carboxylate according toprocedure in Example 1.

¹H NMR: (300 MHz, CDCl₃) δ: 7.49 (s, 1H), 6.96-7.06 (m, 2H), 6.31(s,1H), 5.29 (s,2H), 4.09-4.16 (m, 2H), 2.97 (t, J=7.5 Hz, 2H),2.73-2.81 (m,2H), 2.63 (t, J=7.5 Hz, 2H), 2.27 (s,3H), 2.15 (s,3H), 1.41(t, J=7.2 Hz, 3H), 1.309 (t, J=7.2 Hz, 5H). Mass spectrum (ESI, m/z):Calculated for O₂₄H₂₇ClO₅, 429 (M−H), found 429.

Example 373-(4-{[5-Chloro-2-ethyl-6-(2-methoxyethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 36 substituting 1-bromo-2-methoxyethane for bromoethane instep (a).

¹H NMR: (300 MHz, CDCl₃) δ: 7.46 (s, 1H), 6.95-7.03 (m, 2H), 6.29(s,1H), 5.31 (s, 2H), 4.20 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.5 Hz, 2H),3.36 (s, 3H), 2.95 (t, J=7.8 Hz, 2H), 2.70-2.78 (m, 2H), 2.59 (t, J=7.5Hz, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.28 (t, J=7.5 Hz, 3H), 1.30 (t,J=7.2 Hz, 5H). Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₉ClO₆, 459(M−H), found 459.

Example 383-(4-{[5-Chloro-2-ethyl-6-(2,2,2-trifluoroethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to procedure as described inExample 36 substituting trifluoromethyl trifluoromethanesulfonate forbromoethane and potassium carbonate for cesium carbonate.

¹H NMR: (300 MHz, CDCl₃) δ: 7.51 (s, 1H), 6.94-7.05 (m, 2H), 6.34 (s,1H), 5.32 (s, 2H), 4.42-4.50 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.75-2.82(m, 2H), 2.64(t, J=7.5 Hz, 2H), 2.23 (s,3H), 2.14 (s, 3H), 1.32 (t,J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₄ClF₃O₅,483 (M−H), found 483.

Example 393-(4-{[5-Chloro-2-ethyl-6-(1-methylethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to procedure as described inExample 36 substituting 2-bromopropane for bromoethane.

¹H NMR: (300 MHz, CDCl₃) δ: 7.49 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.95(d, J=8.4 Hz, 1H), 6.31 (s, 1H), 5.27 (s, 2H), 4.51-4.59 (m, 2H), 2.98(t, J=7.5 Hz, 2H), 2.72-2.79 (m, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.24 (s,3H), 2.15 (s, 3H), 1.28-1.36 (m, 9H). Mass spectrum (ESI, m/z):Calculated for C₂₅H₂₉ClO₅, 443 (M−H), found 443.

Example 403-{4-[(6-Ethoxy-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 5-chloro-6-ethoxy-2-ethylbenzofuran-7-carboxylate

Into a 8-mL vial was placed methyl5-chloro-2-ethyl-6-hydroxy-1-benzofuran-7-carboxylate (100 mg, 0.39mmol), acetone (2 mL), bromoethane (0.5 mL) and Cs₂CO₃ (639 mg, 1.96mmol) and the resulting solution was stirred overnight at 60° C. Thereaction was then quenched by the addition of water (5 mL). Theresulting solution was extracted with ethyl acetate (2×5 mL) and theorganic layers combined and concentrated under vacuum. The resultingresidue was purified on a silica gel column with P/E (30/1-20/1) toyield methyl 5-chloro-6-ethoxy-2-ethyl-1-benzofuran-7-carboxylate asyellow oil.

b) (6-Ethoxy-2-ethylbenzofuran-7-yl)methanol

To a solution of methyl5-chloro-6-ethoxy-2-ethyl-1-benzofuran-7-carboxylate (100 mg, 0.35 mmol)in tetrahydrofuran (3 mL) was added LAH (40 mg, 1.05 mmol) in severalbatches. The resulting solution was stirred for 2 h at 25° C. Thereaction was then quenched by the addition of Na₂SO₄.10H₂O (1 g). Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The resulting residue was purified on a silica gel column withethyl acetate/petroleum ether (1/30-1/5) to yield(5-chloro-6-ethoxy-2-ethyl-1-benzofuran-7-yl)methanol and(6-ethoxy-2-ethylbenzofuran-7-yl)methanol as yellow oil.

c)3-{4-[(6-Ethoxy-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting(6-ethoxy-2-ethylbenzofuran-7-yl)methanol according to Example 1.

¹H NMR: (300 MHz, CDCl₃) δ: 7.35 (d, J=8.4 Hz, 1H), 7.01(s, 2H), 6.85(d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.33 (s, 2H), 4.08-4.15 (m, 2H), 2.96(t, J=7.5 Hz, 2H), 2.73-2.80 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.22(s,3H), 2.17 (s, 3H), 1.38-1.43 (t, J=6.9 Hz, 3H), 1.31 (t, J=7.5 Hz,3H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₅O₅, 395 (M−H), found395.

Example 413-(4-{[5-Chloro-2-ethyl-6-(2-methylpropoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to procedure as described inExample 36 substituting 1-bromo-2-methylpropane for bromoethane.

¹H NMR: (300 MHz, CDCl₃) δ: 7.48 (s, 1H), 6.94-7.05 (m, 2H), 6.31 (s,1H), 5.28 (s, 2H), 3.82 (d, J=6.6 Hz, 1H), 2.97 (t, J=7.2 Hz, 2H),2.73-2.80 (m, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.23 (s, 3H), 2.15 (s, 3H),1.31 (t, J=7.5 Hz, 3H), 1.02 (d, J=6.9 Hz, 6H). Mass spectrum (ESI,m/z): Calculated for C₂₆H₃₁ClO₅, 457 (M−H), found 457.

Example 423-(4-{[6-(Benzyloxy)-5-chloro-2-ethyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to procedure as described inExample 36 substituting benzyl bromide for bromoethane. ¹H NMR: (300MHz, CDCl₃) δ: 7.53 (s, 1H), 7.42-7.45 (m, 2H), 7.32-7.34 (m, 2H), 7.01(d, J=8.7 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.34 (s, 1H), 5.25 (s, 2H),5.08 (s, 2H), 2.97 (t, J=7.8 Hz, 2H), 2.74-2.82 (m, 2H), 2.62 (t, J=7.5Hz, 2H), 2.22 (s, 3H), 2.14 (s, 3H), 1.32 (t, J=7.5 Hz, 3H). Massspectrum (ESI, m/z): Calculated for O₂₉H₂₉ClO₅, 491 (M−H), found 491.

Example 433-(4-{[5-Chloro-6-(difluoromethoxy)-2-ethyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Methyl 5-chloro-6-(difluoromethoxy)-2-ethylbenzofuran-7-carboxylate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of CF₂Cl was placed methyl5-chloro-2-ethyl-6-hydroxy-1-benzofuran-7-carboxylate (100 mg, 0.39mmol, prepared as described in Example 20, step(e)), 1,4-dioxane (3 mL),a solution of sodium hydroxide (47 mg, 1.18 mmol) in water(0.2 mL) andtetrabutylammonium iodide (145 mg, 0.39 mmol). The resulting solutionwas stirred overnight at 25° C. The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith P/E (30/1-20/1) to yield methyl5-chloro-6-(difluoromethoxy)-2-ethyl-1-benzofuran-7-carboxylate asyellow oil.

b)3-(4-{[5-Chloro-6-(difluoromethoxy)-2-ethyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to procedure as described inExample 1 using methyl5-chloro-6-(difluoromethoxy)-2-ethyl-1-benzofuran-7-carboxylate.

¹H NMR: (300 MHz, CDCl₃) δ: 7.56 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.94(d, J=8.4 Hz, 1H), 6.61 (t, J=74.7 Hz, 1H), 6.36 (s, 1H), 5.33 (s, 2H),2.97 (t, J=7.5 Hz, 2H), 2.76-2.83 (m, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.23(s, 3H), 2.15 (s, 3H), 1.32 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₃ClF₂O₅, 451 (M−H), found 451.

Example 443-(4-{[6-(Difluoromethoxy)-2-ethyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) (6-(Difluoromethoxy)-2-ethylbenzofuran-7-yl)methanol

To a solution of methyl5-chloro-6-(difluoromethoxy)-2-ethyl-1-benzofuran-7-carboxylate (80 mg,0.26 mmol) in tetrahydrofuran (3 mL) was added LAH (30 mg, 0.79 mmol) inseveral batches. The resulting solution was stirred for 2 h at 25° C.The reaction was then quenched by the addition of Na₂SO₄.10H₂O (1 g).The solids were filtered out. The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith ethyl acetate/petroleum ether (1/30-1/5) to yield[5-chloro-6-(difluoromethoxy)-2-ethyl-1-benzofuran-7-yl]methanol and(6-(difluoromethoxy)-2-ethylbenzofuran-7-yl)methanol as yellow oil.

b)3-(4-{[6-(Difluoromethoxy)-2-ethyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to procedure as described inExample 1 using (6-(difluoromethoxy)-2-ethylbenzofuran-7-yl)methanol.

¹H NMR: (300 MHz, CDCl₃) δ: 7.44 (d, J=8.4 Hz, 1H), 6.95-7.10 (m, 3H),6.51 (t, J=74.9 Hz, 1H), 6.39 (s, 1H), 5.32 (s, 2H), 2.96 (t, J=7.5 Hz,2H), 2.76-2.84 (m, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.23 (s, 3H), 2.15 (s,3H), 1.33 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₄F₂O₅, 418 (M−H), found 418.

Example 453-(2,3-Dimethyl-4-{[2-propyl-5-(3,3,3-trifluoroprop-1-yn-1-yl)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid

a) Ethyl3-(2,3-dimethyl-4-((2-propyl-5-(3,3,3-trifluoroprop-1-yn-1-yl)benzofuran-7-yl)methoxy)phenyl)propanoate

To a solution of disopropylamine (128 mg) in tetrahydrofuran (10 mL) at−78° C. was added n-BuLi (0.5 mL, 2.5N) and the resulting solution wasstirred for 15 min. To this solution was added2-bromo-3,3,3-trifluoroprop-1-ene (100.6 mg, 0.58 mmol), and ZnCl₂.TMEDA(159 mg), and the mixture was stirred for 30 min at −78° C. Ethyl3-[4-[(5-iodo-2-propyl-1-benzofuran-7-y)methoxy]-2,3-dimethylphenyl]propanoate(200 mg, 0.38 mmol, prepared as described in Example 18) and Pd(PPh₃)₄(22 mg, 0.02 mmol) were then added and the mixture stirred for 30 min atroom temperature and then at 80° C. overnight. The resulting mixture wasconcentrated under vacuum, diluted with ethyl acetate (40 mL), andwashed with brine (3×10 mL). The resulting residue was dried overanhydrous sodium sulfate and concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1:5) to yield ethyl3-(2,3-dimethyl-4-((2-propyl-5-(3,3,3-trifluoroprop-1-yn-1-yl)benzofuran-7-yl)methoxy)phenyl)propanoate.

b)3-(2,3-Dimethyl-4-{[2-propyl-5-(3,3,3-trifluoroprop-1-yn-1-yl)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid

The title compound was prepared by hydrolysis of the ester prepared instep (b) above according to the procedure as described in Example 1.

¹H NMR: (400 MHz, CD₃OD) δ 7.79 (s, 1H), 7.56 (s, 1H), 6.99 (d, J=8.4Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 5.33 (s, 2H), 2.91 (t,J=8.0 Hz, 2H), 2.82 (t, J=7.6 Hz, 2H), 2.51 (t, J=8.0 Hz, 2H), 2.25 (s,3H), 1.86-1.63 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). Mass spectrum (ESI,m/z): Calculated for C₂₆H₂₅F₃O₄, 457 (M−H), found 457.

Example 463-{4-[(5-Chloro-2-ethyl-6-phenoxy-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 5-chloro-2-ethyl-6-phenoxybenzofuran-7-carboxylate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl5-chloro-2-ethyl-6-hydroxy-1-benzofuran-7-carboxylate (300 mg, 1.18mmol, prepared in Example 20 step f), CH₃CN (8 mL),2-(trimethylsilyl)phenyl trifluoromethanesulfonate (703 mg, 2.36 mmol),and CsF (535 mg, 3.54 mmol) the resulting mixture was heated to refluxovernight. The reaction was then quenched by the addition of water (10mL). The resulting solution was extracted with ethyl acetate (2×10 mL)acetate and the organic layers combined and concentrated under vacuum.The resulting residue was purified on a silica gel column with P/E(30/1-10/1) to yield methyl5-chloro-2-ethyl-6-phenoxy-1-benzofuran-7-carboxylate as yellow oil.

b)3-{4-[(5-Chloro-2-ethyl-6-phenoxy-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl5-chloro-2-ethyl-6-phenoxy-1-benzofuran-7-carboxylate according to theprocedure as described in Example 1.

¹H NMR: (300 MHz, CDCl₃) δ: 7.57 (s, 1H), 721-7.27 (m, 2H), 6.92-7.01(m, 2H), 6.78-6.84 (m, 3H), 6.38 (s, 1H), 5.16 (s, 2H), 2.92 (t, J=7.5Hz, 2H), 2.77-2.84 (m, 2H), 2.57 (t, J=7.5 Hz, 2H), 2.20 (s, 3H), 2.11(s, 3H), 1.34 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculatedfor O₂₅H₂₇ClO₅, 501 (M+Na), found 501.

Example 473-(4-{[5-(Difluoromethoxy)-2-methyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Methyl 5-methoxy-2-methylbenzofuran-7-carboxylate

Into a 150-mL sealed tube was placed methyl3-bromo-2-hydroxy-5-methoxybenzoate (3.0 g, 11.49 mmol, prepared asdescribed in Example 33 step a), Pd(PPh₃)₂Cl₂ (0.805 g), CuI (219 mg,1.15 mmol), TEA (2.33 g, 23.03 mmol) and N,N-dimethylformamide (50 mL).The resulting residue was cooled to −78° C. and prop-1-yne (923 mg,23.04 mmol) was introduced. The resulting mixture was stirred overnightat 80° C. The resulting solution was diluted with EtOAc and washed withbrine (3×50 mL). The resulting residue was dried over anhydrous sodiumsulfate, concentrated, and the residue was purified by silica gelchromatography to yield methyl5-methoxy-2-methyl-1-benzofuran-7-carboxylate as a yellow solid.

b) Methyl 5-hydroxy-2-methylbenzofuran-7-carboxylate

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl5-methoxy-2-methyl-1H-indene-7-carboxylate (500 mg, 2.29 mmol),dichloromethane (20 mL). To the resulting mixture was then added BBr₃(1.13 g) at −78° C. The resulting solution was stirred for 30 min atroom temperature. The reaction was then quenched by the addition ofwater (5 mL). The resulting solution was diluted with DCM (30 mL). Theresulting mixture was washed with brine (3×10 mL). The resulting residuewas dried over anhydrous sodium sulfate. The solids were filtered out.The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1:3) to yield methyl 5-hydroxy-2-methyl-1H-indene-7-carboxylateas a yellow solid.

c) Methyl 5-(difluoromethoxy)-2-methylbenzofuran-7-carboxylate

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of chlorodifluoromethane was placed methyl5-hydroxy-2-methyl-1-benzofuran-7-carboxylate (310 mg, 1.50 mmol),1,4-dioxane (10 mL), water (1 mL), sodium hydroxide (182.4 mg, 4.56mmol) and tetrabutylammonium iodide (561 mg, 1.52 mmol). The resultingsolution was stirred overnight at room temperature. The resultingmixture was concentrated under vacuum. The resulting solution wasdiluted with ethyl acetate (50 mL). The resulting mixture was washedwith brine (3×10 mL). The solid was dried in an oven under reducedpressure. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:4) to yieldmethyl 5-(difluoromethoxy)-2-methyl-1-benzofuran-7-carboxylate as alight yellow solid.

d)3-(4-{[5-(Difluoromethoxy)-2-methyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting methyl5-(difluoromethoxy)-2-methylbenzofuran-7-carboxylate according toExample 1.

¹H NMR: (400 MHz, CD₃Cl) δ: 7.19 (d, J=4.8 Hz, 2H), 7.01 (d, J=8.0 Hz,1H), 6.82 (d, J=11.2 Hz, 1H), 6.50 (t, J=74.4 Hz, 1H), 6.41 (s, 1H),5.32 (s, 2H), 2.98 (t, J=8.0 Hz, 2H), 2.62 (t, J=8.0 Hz, 2H), 2.49 (s,3H), 2.27 (s, 6H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂F₂O₅,403 (M−H), found 403.

Example 483-(4-{[5-(Difluoromethoxy)-2-propyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 47 substituting pent-1-yne for prop-1-yne in step (a).

¹H NMR: (300 MHz, CD₃Cl) δ: 7.19 (d, J=5.4 Hz, 2H), 6.99 (d, J=8.4 Hz,1H), 6.82 (d, J=8.4 Hz, 1H), 6.49 (d, J=74.4 Hz, 1H), 6.41 (s, 1H), 5.31(s, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.8Hz, 2H), 2.25 (s, 6H), 1.82-1.75 (m, 2H),1.02 (t, J=7.5 Hz, 3H). Massspectrum (ESI, m/z): Calculated for C₂₄H₂₆F₂O₅, 431 (M−H), found 431.

Example 493-{4-[(5-Chloro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 3-bromo-5-chloro-2-hydroxybenzoate

Into a 1-L round-bottom flask was placed methyl5-chloro-2-hydroxybenzoate (16 g, 85.75 mmol), methanol (200 mL) and Br₂(16.5 g, 103.25 mmol) and the resulting mixture was stirred for 10 minat 20° C. The solids were collected by filtration, then washed withmethanol to yield methyl 3-bromo-5-chloro-2-hydroxybenzoate as a whitepowder.

b) Methyl 5-chloro-2-methylbenzofuran-7-carboxylate

Into a 80-mL tube was placed methyl 3-bromo-5-chloro-2-hydroxybenzoate(3 g, 11.30 mmol), Pd(Ph₃P)₂Cl₂ (0.791 g), CuI (215 mg, 1.13 mmol), TEA(2.28 g, 22.53 mmol), N,N-dimethylformamide (30 mL), and prop-1-yne (950mg, 23.71 mmol). The resulting solution was stirred overnight at 80° C.The resulting mixture was extracted with ethyl acetate (100 mL), and thewashed with brine. The resulting mixture was concentrated and theresidue was purified on a silica gel column to yield methyl5-chloro-2-methyl-1-benzofuran-7-carboxylate as a yellow solid.

c)3-{4-[(5-Chloro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl5-chloro-2-methyl-1-benzofuran-7-carboxylate according to the procedureas described in Example 1.

¹H NMR: (300 MHz, CD₃OD) δ: 7.39 (d, J=1.8, 1H), 7.24 (d, J=1.8, 1H),6.93 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.44 (s, 1H), 5.24 (s,2H), 2.89-2.83 (m, 2H), 2.48-2.43 (m, 5H), 2.20 (s, 3H), 2.17 (s, 3H).Mass spectrum (ESI, m/z): Calculated for O₂₁H₂₁ClO₄, 371 (M−H), found371.

Example 503-(4-{[5-(1,1-Difluoroethyl)-2-propyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Ethyl3-(4-((5-acetyl-2-propylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 5-mL flask was placed ethyl3-[4-[(5-iodo-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(20 mg, 0.04 mmol, prepared as described in Example 18),N,N-dimethylformamide (1 mL), LiCl (8 mg), DIPEA (10 mg), Pd₂(dba)₃ (0.5mg), and acetyl acetate (20 mg, 0.20 mmol). The resulting mixture wasirradiated with microwave radiation for 1 h at 150° C. The resultingsolution was diluted with ethyl acetate (20 mL), and washed with brine(3×10 mL). The resulting residue was dried over anhydrous sodium sulfateand solids were filtered out. The resulting mixture was concentratedunder vacuum and the residue was purified by silica gel chromatographyto yield ethyl3-[4-[(5-acetyl-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoateas a white solid.

b) Ethyl3-(4-((5-(1,1-difluoroethyl)-2-propylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 8-mL vial purged and maintained with an inert atmosphere ofnitrogen was placed ethyl3-[4-[(5-acetyl-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoate(170 mg, 0.39 mmol) and DAST (0.5 mL) in [C₈min][PF₆] (2 mL). Theresulting solution was stirred overnight at 55° C. The resultingsolution was diluted with ethyl acetate (50 mL). The resulting mixturewas washed with brine (3×10 mL). The resulting residue was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether (1:3)to yield ethyl3-(4-[[5-(1,1-difluoroethyl)-2-propyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoateas colorless oil.

c)3-(4-{[5-(1,1-Difluoroethyl)-2-propyl-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

Into a 8-mL vial was placed ethyl3-(4-[[5-(1,1-difluoroethyl)-2-propyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoate(30 mg, 0.07 mmol), LiOH (30 mg, 1.25 mmol), tetrahydrofuran (2 mL), andwater (2 mL). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. The pHof the solution was adjusted to pH 4-5 with hydrogen chloride (1 mol/L).The resulting solution was extracted with ethyl acetate (3×20 mL) andthe organic layers combined and concentrated under vacuum to yield 23-(4-[[5-(1,1-difluoroethyl)-2-propyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a white solid.

¹H NMR: (400 MHz, CD₃Cl) δ 7.63 (s, 1H), 7.54 (s, 1H), 7.02 (t, J=4.8Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.46 (s, 1H), 5.34 (s, 2H), 2.98 (t,J=8.0 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.63 (t, J=5.4 Hz, 2H), 2.26 (d,J=4.4 Hz, 6H), 1.99 (t, J=18.0 Hz, 3H), 1.85-1.75 (m, 2H), 1.03 (t,J=7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₈F₂O₄, 429(M−H), found 429.

Example 513-{2,3-Dimethyl-4-[(6-methylfuro[2,3-f][1,3]benzodioxol-4-yl)methoxy]phenyl}propanoicacid

a) 5-(Methoxymethoxy)benzo[d][1,3]dioxole

Into a 250-mL round-bottom flask was placed2,3-dihydro-1,4-benzodioxin-6-ol (6 g, 39.44 mmol), tetrahydrofuran (100mL). To the resulting mixture was then added sodium hydride (1.56 g,65.00 mmol) at 0-5° C. The resulting residue was stirred for 30 min at0° C. To the resulting mixture was then added bromo(methoxy)methane(8.08 g, 64.66 mmol). The resulting solution was stirred overnight atroom temperature. The resulting mixture was concentrated under vacuum.The resulting solution was diluted with ethyl acetate (100 mL). Theresulting mixture was washed with brine (3×50 mL). The resulting residuewas dried over anhydrous sodium sulfate. The solids were filtered out.The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1:3) to yield 6-(methoxymethoxy)-2,3-dihydro-1,4-benzodioxine ascolorless oil.

b) 5-(Methoxymethoxy)benzo[d][1,3]dioxole-4-carbaldehyde

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed 5-(methoxymethoxy)-2H-1,3-benzodioxole(6.6 g, 36.23 mmol), tetrahydrofuran (150 mL), BuLi (22 mL, 36.23 mmol),TMEDA (4.26 g, 36.66 mmol) and N,N-dimethylformamide (4.02 g). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of water (1 mL). Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with ethyl acetate (200 mL). The resulting mixture waswashed with brine (3×40 mL). The solid was dried in an oven underreduced pressure. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:3) to yield5-(methoxymethoxy)-2H-1,3-benzodioxole-4-carbaldehyde as a yellow solid.

c) 5-Hydroxybenzo[d][1,3]dioxole-4-carbaldehyde

Into a 250-mL round-bottom flask was placed5-(methoxymethoxy)-2H-1,3-benzodioxole-4-carbaldehyde (7 g, 33.30 mmol),dichloromethane (100 mL) and trifluoroacetic acid (5 mL). The resultingsolution was stirred for 1 h at 0° C. The resulting solution was dilutedwith DCM (100 mL). The resulting mixture was washed with brine (3×50mL). The resulting residue was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The resulting residue was purified on a silica gel column withethyl acetate/petroleum ether (1:1) to yield5-hydroxy-2H-1,3-benzodioxole-4-carbaldehyde as colorless oil.

d) 6-Bromo-5-hydroxybenzo[d][1,3]dioxole-4-carbaldehyde

Into a 250-mL round-bottom flask was placed5-hydroxy-2H-1,3-benzodioxole-4-carbaldehyde (3.1 g, 18.66 mmol),methanol (150 mL) and Br₂ (3.53 g, 22.09 mmol). The resulting solutionwas stirred for 30 min at room temperature. The resulting mixture wasconcentrated under vacuum. The resulting solution was diluted with ethylacetate (150 mL). The resulting mixture was washed with Na₂SO₃ (3×40mL). The resulting residue was dried over anhydrous sodium sulfate. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1:2) to yield 6-bromo-5-hydroxy-2H-1,3-benzodioxole-4-carbaldehyde as ayellow solid.

e) 6-Methyl-[1,3]dioxolo[4,5-f]benzofuran-4-carbaldehyde

Into a 100-mL sealed tube was placed6-bromo-5-hydroxy-2H-1,3-benzodioxole-4-carbaldehyde (1.1 g, 4.49 mmol),N,N-dimethylformamide (30 mL), CuI (85 mg, 0.45 mmol), TEA (907 mg, 8.96mmol) and Pd(PPh₃)₂Cl₂(314 mg, 0.45 mmol). To the resulting mixture wasthen added prop-1-yne (359 mg, 8.96 mmol) at −78° C. The resultingsolution was stirred overnight at 80° C. in an oil bath. The resultingsolution was diluted with ethyl acetate (100 mL). The resulting mixturewas washed with sodium chloride(ac) (3×20 mL). The resulting residue wasdried over anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1:3) to yield 6-methyl-[1,3]dioxolo[4,5-f]benzofuran-4-carbaldehyde ascolorless oil.

f) (6-Methyl-[1,3]dioxolo[4,5-f]benzofuran-4-yl)methanol

Into a 8-mL vial was placed6-methyl-[1,3]dioxolo[4,5-f]benzofuran-4-carbaldehyde (50 mg, 0.24mmol), tetrahydrofuran (2 mL) and LiAlH₄ (28 mg, 0.74 mmol) at 0-5° C.The resulting solution was stirred for 30 min at 0° C. The reaction wasthen quenched by the addition of water (1 mL). The resulting solutionwas diluted with ethyl acetate (20 mL). The resulting mixture was washedwith brine (3×10 mL). The resulting residue was dried over anhydroussodium sulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:3) to yield(6-methyl-[1,3]dioxolo[4,5-f]benzofuran-4-yl)methanol as a yellow solid.

d)3-{2,3-Dimethyl-4-[(6-methylfuro[2,3-f][1,3]benzodioxol-4-yl)methoxy]phenyl}propanoicacid

The title compound was prepared by reacting6-methyl-[1,3]dioxolo[4,5-f]benzofuran-4-yl)methanol according to theprocedures as described in Example 1.

¹H NMR: (300 MHz, CDCl₃) δ: 7.01 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz,1H), 6.85 (s, 1H), 6.27 (s, 1H), 6.00 (s, 2H), 5.27 (s, 2H), 2.96 (t,J=7.5 Hz, 2H), 2.64-2.59 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.20 (s,3H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂O₆, 381 (M−H), found381.

Example 523-{2,3-Dimethyl-4-[(2-methyl-5-prop-1-yn-1-yl-1-benzofuran-7-yl)methoxy]phenyl}propanoicacid

a) 2-Methyl-5-(prop-1-yn-1-yl)benzofuran-7-carbaldehyde

Into a 5-mL sealed tube was placed 2-hydroxy-3,5-diiodobenzaldehyde (500mg, 1.34 mmol), Cu₂O (115 mg, 0.80 mmol) and pyridine (3 mL). This wasfollowed by the addition of prop-1-yne (160 mg, 3.99 mmol) dropwise withstirring at −78° C. The resulting solution was stirred overnight at 120°C. The resulting solution was diluted with ethyl acetate (20 mL). Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The resulting residue was purified on a silica gel column withethyl acetate/petroleum ether (10/90). The collected fractions werecombined and concentrated under vacuum to yield2-methyl-5-(prop-1-yn-1-yl)-1-benzofuran-7-carbaldehyde as colorlessoil.

b) (2-Methyl-5-(prop-1-yn-1-yl)benzofuran-7-yl)methanol

Into a 100-mL round-bottom flask was placed2-methyl-5-(prop-1-yn-1-yl)-1-benzofuran-7-carbaldehyde (50 mg, 0.25mmol), tetrahydrofuran (10 mL) and LAH (19 mg, 0.50 mmol) in portions at0° C. The resulting solution was stirred for 2 h at 25° C. The reactionwas then quenched by the addition of Na₂SO₄.10H₂O (100 mg). The solidswere filtered out. The resulting mixture was concentrated under vacuum.The resulting residue was purified on a silica gel column with ethylacetate/petroleum ether (40/60). The collected fractions were combinedand concentrated under vacuum to yield(2-methyl-5-(prop-1-yn-1-yl)benzofuran-7-yl)methanol as colorless oil.

c)3-{2,3-Dimethyl-4-[(2-methyl-5-prop-1-yn-1-yl-1-benzofuran-7-yl)methoxy]phenyl}propanoicacid

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed(2-methyl-5-(prop-1-yn-1-yl)benzofuran-7-yl)methanol (70 mg, 0.35 mmol),ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (116 mg, 0.52 mmol),Bu₃P (177 mg), ADDP (185 mg, 0.74 mmol) and toluene (30 mL). Theresulting solution was stirred overnight at 60° C. The resulting mixturewas concentrated under vacuum. The resulting solution was diluted withdiethyl ether (30 mL). The solids were filtered out. The resultingmixture was concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(10/90). The collected fractions were combined and concentrated undervacuum to yield ethyl3-(2,3-dimethyl-4-[[2-methyl-5-(prop-1-yn-1-yl)-1-benzofuran-7-yl]methoxy]phenyl)propanoateas colorless oil.

¹H NMR: (300 MHz, CD₃OD) δ: 7.44 (s, 1H), 7.30 (s, 1H), 6.98 (d, J=6.3Hz, 1H), 6.83 (d, J=6.3 Hz, 1H), 6.45 (s, 1H), 5.26 (s, 2H), 2.91 (t,J=5.7 Hz,2H), 2.51 (t, J=6 Hz, 2H), 2.47 (s, 3H), 2.28 (s, 3H), 2.25 (s,3H), 2.02 (s,3H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₄O₄, 375(M−H), found 375.

Example 533-{4-[(5-Chloro-2,6-dimethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 20 substituting prop-1-yne for but-1-yne in step (d).

¹H NMR: (300 MHz, CDCl₃) δ: 7.62 (s, 1H), 6.93-7.05 (m, 2H), 6.32 (s,1H), 5.32 (s, 2H), 2.98 (t, J=7.2 Hz, 2H), 2.63 (t, J=8.4 Hz, 2H), 2.51(s, 3H), 2.45 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H). Mass spectrum (ESI,m/z): Calculated for C₂₂H₂₃ClO₄, 385 (M−H), found 385.

Example 543-{4-[(5-Chloro-2₁6-dimethyl-1-benzofuran-7-yl)methoxy]-3,5-difluorophenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 53 substituting ethyl3-(3,5-difluoro-4-hydroxyphenyl)propanoate (prepared as described inU.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011) for ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate.

¹H NMR: (300 MHz, CD₃OD) δ: 7.49 (s, 1H), 6.84 (d, J=9.3 Hz, 2H), 6.36(s, 1H), 5.47 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.54-2.59 (m, 5H), 2.39(s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₇ClF₂O₄, 393(M−H), found 393.

Example 553-{4-[(2,2-Difluoro-6-methylfuro[2,3-f][1,3]benzodioxol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 2,2-Difluorobenzo[d][1,3]dioxol-5-ol

Into a 250-mL round-bottom flask was placed(2,2-difluoro-2H-1,3-benzodioxol-5-yl)boronic acid (5 g, 24.76 mmol),H₂O₂ (50 mL) and tetrahydrofuran (100 mL). The resulting solution wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The resulting solution was extracted withethyl acetate (3×30 mL) acetate and the organic layers combined andconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:1) to yield2,2-difluoro-2H-1,3-benzodioxol-5-ol as yellow oil.

b) 2,2-Difluoro-5-(methoxymethoxy)benzo[d][1,3]dioxole

Into a 250-mL round-bottom flask was placed2,2-difluoro-2H-1,3-benzodioxol-5-ol (4.2 g, 24.12 mmol),tetrahydrofuran (100 mL) and sodium hydride (1.5 g, 62.50 mmol) and themixture was stirred for 1 hr at 0° C. Bromo(methoxy)methane (4.49 g,35.93 mmol) was then added and the resulting solution was stirredovernight at room temperature. The reaction was then quenched by theaddition of water (5 mL). The resulting mixture was concentrated undervacuum. The resulting solution was diluted with ethyl acetate (100 mL).The resulting mixture was washed with brine (3×30 mL). The resultingresidue was dried over anhydrous sodium sulfate. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1:3) to yield2,2-difluoro-5-(methoxymethoxy)-2H-1,3-benzodioxole as yellow oil.

c) 2,2-Difluoro-5-(methoxymethoxy)benzo[d][1,3]dioxole-4-carbaldehyde

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed2,2-difluoro-5-(methoxymethoxy)-2H-1,3-benzodioxole (4.4 g, 20.17 mmol),tetrahydrofuran (50 mL). To the resulting mixture was then added n-BuLi(18.9 mL) and the mixture was stirred for 15 min at −78° C. To theresulting mixture was then added TMEDA (2.3 g, 19.79 mmol) andN,N-dimethylformamide (2.2 g, 30.10 mmol) and the resulting solution wasstirred overnight at room temperature. The reaction was then quenched bythe addition of water (1 mL). The resulting mixture was concentratedunder vacuum. The resulting solution was diluted with ethyl acetate (150mL). The resulting mixture was washed with brine (3×40 mL). Theresulting residue was dried over anhydrous sodium sulfate. The solidswere filtered out. The resulting mixture was concentrated under vacuum.The resulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1:2) to yield2,2-difluoro-5-(methoxymethoxy)-2H-1,3-benzodioxole-4-carbaldehyde asyellow oil.

d) 2,2-Difluoro-5-(methoxymethoxy)benzo[d][1,3]dioxole-4-carboxylic acid

Into a 250-mL round-bottom flask was placed2,2-difluoro-5-(methoxymethoxy)-2H-1,3-benzodioxole-4-carbaldehyde (4.0g, 16.25 mmol), Ag₂O (5.6 g) and sodium hydroxide (5% aq) (100 mL). Theresulting solution was stirred overnight at room temperature. The solidswere filtered out. The pH value of the solution was adjusted to pH 2-3with hydrogen chloride (6 mol/L). The resulting solution was extractedwith ethyl acetate (3×50 mL) and the organic layers combined and driedover anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1:1) to yield2,2-difluoro-5-(methoxymethoxy)-2H-1,3-benzodioxole-4-carboxylic acid asyellow oil.

e) Methyl2,2-difluoro-5-(methoxymethoxy)benzo[d][1,3]dioxole-4-carboxylate

Into a 250-mL round-bottom flask was placed2,2-difluoro-5-(methoxymethoxy)-2H-1,3-benzodioxole-4-carboxylic acid(3.2 g, 12.21 mmol), methanol (100 mL) and azidotrimethylsilane (2.08 g,18.05 mmol). The resulting solution was stirred for 3 h at 0° C. Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with ethyl acetate (100 mL). The resulting mixture waswashed with brine (3×40 mL). The resulting residue was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether (1:3)to yield methyl2,2-difluoro-5-(methoxymethoxy)-2H-1,3-benzodioxole-4-carboxylate as ayellow solid.

f) Methyl 2,2-difluoro-5-hydroxybenzo[d][1,3]dioxole-4-carboxylate

Into a 250-mL round-bottom flask was placed methyl2,2-difluoro-5-(methoxymethoxy)-2H-1,3-benzodioxole-4-carboxylate (3.0g, 10.86 mmol), dichloromethane (100 mL) and CF₃COOH (10 mL) was thenadded at 0-5° C. in an ice/water bath. The resulting solution wasstirred for 2 h at 0° C. The resulting mixture was washed with brine(3×50 mL). The resulting residue was dried over anhydrous sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:1) to yieldmethyl 2,2-difluoro-5-hydroxy-2H-1,3-benzodioxole-4-carboxylate as ayellow solid.

d) Methyl6-bromo-2,2-difluoro-5-hydroxybenzo[d][1,3]dioxole-4-carboxylate

Into a 100-mL round-bottom flask was placed methyl2,2-difluoro-5-hydroxy-2H-1,3-benzodioxole-4-carboxylate (800 mg, 3.45mmol), methanol (30 mL) and Br₂ (707 mg, 4.42 mmol) was then added at0-5° C. in an ice/water bath. The resulting solution was stirred for 3 hat 0° C. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with ethyl acetate (50 mL). The resultingmixture was washed with brine (3×15 mL). The resulting residue was driedover anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1:2) to yield methyl6-bromo-2,2-difluoro-5-hydroxy-2H-1,3-benzodioxole-4-carboxylate as abrown solid.

h) Methyl2,2-difluoro-6-methyl-[1,3]dioxolo[4,5-f]benzofuran-4-carboxylate

Into a 50-mL sealed tube was placed methyl6-bromo-2,2-difluoro-5-hydroxy-2H-1,3-benzodioxole-4-carboxylate (760mg, 2.44 mmol), CuI (47 mg, 0.25 mmol), Pd(PPh₃)₂Cl₂ (172 mg, 0.25mmol), TEA (495 mg, 4.89 mmol) and N,N-dimethylformamide (15 mL). To theresulting mixture was then added prop-1-yne (196 mg, 4.89 mmol) at −78°C. The resulting solution was stirred overnight at 75° C. The resultingsolution was diluted with ethyl acetate (50 mL). The resulting mixturewas washed with brine (3×15 mL). The resulting residue was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether (1:3)to yield methyl2,2-difluoro-6-methyl-[1,3]dioxolo[4,5-f]benzofuran-4-carboxylate as ayellow solid.

i)3-{4-[(2,2-Difluoro-6-methylfuro[2,3-f][1,3]benzodioxol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl2,2-difluoro-6-methyl-[1,3]dioxolo[4,5-f]benzofuran-4-carboxylateaccording to procedure in Example 20.

¹H NMR: (300 MHz, CD₃OD) δ: 7.26 (s, 1H), 6.99 (d, J=6.3 Hz, 2H), 6.90(d, J=6.3 Hz, 2H), 5.35 (s, 2H), 2.91 (t, J=6.0 Hz, 2H), 2.56-2.47 (m,5H), 2.21 (s, 3H), 2.14 (s, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₂H₂₀F₂O₆, 417 (M−H), found 417.

Example 563-{2,3-Dimethyl-4-[(7-methyl-2,3-dihydrofuro[2,3-g][2,3]benzodioxin-5-yl)methoxy]phenyl}propanoicacid

The title compound was prepared according to the procedure described inExample 55 substituting 2,3-dihydro-1,4-benzodioxin-6-ol for2,2-difluorobenzo[d][1,3]dioxol-5-ol in step (b).

¹H NMR: (300 MHz, CD₃OD) δ: 6.98-6.89 (m, 3H), 6.28 (s, 1H), 5.22 (s,2H), 4.27-4.22 (m, 4H), 2.89 (t, J=7.5 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H),2.38 (s, 3H), 2.281 (s, 3H), 2.03 (s, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₄O₆, 395 (M−H), found 395.

Example 573-{4-[(5-Chloro-2-methyl-1-benzothiophen-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Ethyl 2-((2-bromo-4-chlorophenyl)thio)propanoate

Into a 250-mL round-bottom flask was placed2-bromo-4-chlorobenzene-1-thiol (5 g, 22.37 mmol), acetone (100 mL),ethyl 2-bromopropanoate (12 g, 66.29 mmol), and potassium carbonate (9.2g, 66.57 mmol). The resulting solution was heated to reflux overnight.The reaction was then quenched by the addition of water (200 mL). Theresulting solution was extracted with ethyl acetate (2×200 mL) and theorganic layers combined and concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1/100-1/10) to yield ethyl2-[(2-bromo-4-chlorophenyl)sulfanyl]propanoate as colorless oil.

b) 2-((2-Bromo-4-chlorophenyl)thio)propanal

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed ethyl2-[(2-bromo-4-chlorophenyl)sulfanyl]propanoate (4 g, 12.36 mmol) anddichloromethane (100 mL). To the resulting mixture was then addedDIBAL-H (24 mL) at −70° C. The resulting solution was stirred for 30 minat −70° C. The reaction was then quenched by the addition of water (40mL). The solids were filtered out. The resulting solution was extractedwith ethyl acetate (3×50 mL) and the organic layers combined andconcentrated under vacuum. The resulting residue was purified on asilica gel column with EtOAc/PE(1/100-1/30) to yield2-[(2-bromo-4-chlorophenyl)sulfanyl]propanal as colorless oil.

c) 7-Bromo-5-chloro-2-methylbenzo[b]thiophene

Into a 100-mL round-bottom flask was placed PPA (10 mL) and2-[(2-bromo-4-chlorophenyl)sulfanyl]propanal (1.2 g, 4.29 mmol) and themixture was heated at 150° C. for 45 min. The resulting residue wascooled to room temperature. The reaction was then quenched by theaddition of water (20 mL). The resulting solution was extracted withwthyl acetate (2×20 mL) and the organic layers combined and concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith ethyl acetate/petroleum ether (1/100-1/10) to yield7-bromo-5-chloro-2-methyl-1-benzothiophene as a yellow solid.

d) Methyl 5-chloro-2-methylbenzo[b]thiophene-7-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed7-bromo-5-chloro-2-methyl-1-benzothiophene (900 mg, 3.44 mmol), methanol(20 mL), triethylamine (1 g, 9.88 mmol) and Pd(dppf)Cl₂ (504 mg, 0.69mmol). The resulting solution was stirred overnight at 60° C. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified on a silica gel column with P/E (100/1-10/1) to yieldmethyl 5-chloro-2-methyl-1-benzothiophene-7-carboxylate as a whitesolid.

e)3-{4-[(5-Chloro-2-methyl-1-benzothiophen-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 20 from 5-chloro-2-methyl-1-benzothiophene-7-carboxylate.

¹ H NMR: (300 MHz, CD₃OD) δ: 7.61 (s, 1H), 7.31 (s, 1H), 7.01 (s, 1H),6.91 (d, J=8.1 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 5.16 (s, 2H), 2.85 (t,J=7.5 Hz, 2H), 2.55 (s, 3H), 2.45 (t, J=7.5 Hz, 2H), 2.15 (s, 6H). Massspectrum (ESI, m/z): Calculated for C₂₁H₂₁ClO₃S, 387 (M−H), found 387.

Example 583-{4-[(5-Chloro-2-methyl-1-benzothiophen-7-yl)methoxy]-3,5-difluorophenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 57 substituting ethyl3-(3,5-difluoro-4-hydroxyphenyl)propanoate (prepared as described inU.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011) for ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate.

¹ H NMR: (300 MHz, CD₃OD) δ: 7.62 (s, 1H), 7.28 (s, 1H), 7.00 (s, 1H),6.81-6.89 (m, 2H), 5.22 (s, 2H), 2.82 (t, J=7.2 Hz, 2H), 2.52-2.57 (m,5H), 1.71-1.80 (m, 2H). Mass spectrum (ESI, m/z): Calculated forC₁₉H₁₅ClF₂O₃S, 395 (M−H), found 395.

Example 593-{4-[(5-Chloro-2-methyl-1-benzothiophen-7-yl)methoxy]-3,5-difluorophenyl}propan-1-ol

To a solution of ethyl3-[4-[(5-chloro-2-methyl-1-benzothiophen-7-yl)methoxy]-3,5-difluorophenyl]propanoate(100 mg, 0.24 mmol, prepared as described in Example 58) intetrahydrofuran (5 mL) was added LAH (8.9 mg, 0.23 mmol). The resultingsolution was stirred for 30 min at 0° C. The reaction was then quenchedby the addition of Na₂SO₄.10H₂O (500 mg). The solids were filtered out.The resulting mixture was concentrated under vacuum and the resultingresidue was purified by reversed-phase-(C₁₈)-HPLC to yield3-[4-[(5-chloro-2-methyl-1-benzothiophen-7-yl)methoxy]-3,5-difluorophenyl]propan-1-olas a white solid. ¹H NMR: (300 MHz, CD₃OD) δ: 7.70 (s, 1H), 7.40 (s,1H), 7.01 (s, 1H), 6.77-6.85 (m, 2H), 5.23 (s, 2H), 3.51 (t, J=6.3 Hz,2H), 2.56-2.63 (m, 5H), 1.71-1.80 (m, 2H).

Example 603-[2,3-Dimethyl-4-({2-methyl-5-[3-(methylsulfonyl)prop-1-yn-1-yl]-1-benzofuran-7-yl}methoxy)phenyl]propanoicacid

a)3-(2,3-Dimethyl-4-((2-methyl-5-(3-(methylthio)prop-1-yn-1-yl)benzofuran-7-yl)methoxy)phenyl)propanoicacid

To a solution of ethyl3-[2,3-dimethyl-4-([2-methyl-5-[3-(methylsulfanyl)prop-1-yn-1-yl]-1-benzofuran-7-yl]methoxy)phenyl]propanoate(100 mg, 0.22 mmol, prepared as described in Example 61) intetrahydrofuran (2 mL) was added a solution of LiOH (100 mg, 4.18 mmol)in water (2 mL). The resulting residue was stirred overnight at 25° C.and the pH was adjusted to pH 5 with hydrogen chloride (2 mol/L). Theresulting residue was extracted with ethyl acetate (3×10 mL) and theorganic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum to yield3-[2,3-dimethyl-4-([2-methyl-5-[3-(methylsulfanyl)prop-1-yn-1-yl]-1-benzofuran-7-yl]methoxy)phenyl]propanoicacid as yellow oil.

b)3-[2,3-Dimethyl-4-({2-methyl-5-[3-(methylsulfonyl)prop-1-yn-1-yl]-1-benzofuran-7-yl}methoxy)phenyl]propanoicacid

Into a 50-mL round bottom flask was placed3-[2,3-dimethyl-4-([2-methyl-5-[3-(methylsulfanyl)prop-1-yn-1-yl]-1-benzofuran-7-yl]methoxy)phenyl]propanoicacid (120 mg, 0.28 mmol), dichloromethane (3 mL) and m-CPBA (98 mg, 0.57mmol). The resulting solution was stirred for 1 h at 25° C. Theresulting mixture was concentrated under vacuum and purified byRP-C18-HPLC to yield3-(4-[[5-(3-methanesulfonylprop-1-yn-1-yl)-2-methyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a white solid.

¹H NMR: (300 MHz, CD₃OD) δ: 7.61 (s, 1H), 7.44 (s, 1H), 7.05 (s, 1H),6.97 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.52 (s, 1H), 5.29 (s,2H), 3.56 (s, 2H), 3.09 (s, 3H), 2.91 (t, J=7.5 Hz, 2H), 2.42-2.60 (m,5H), 2.32 (s, 3H), 2.21 (s, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₅H₂₆O₆S, 481 (M+Na), found 481.

Example 613-[2,3-Dimethyl-4-({2-methyl-5-[3-(methylsulfonyl)propyl]-1-benzofuran-7-yl}methoxy)phenyl]propanoicacid

a) 5-Iodo-2-methylbenzofuran-7-carbaldehyde

Into a 50-mL sealed tube was placed 2-hydroxy-3,5-diiodobenzaldehyde (2g, 5.35 mmol), pyridine (10 mL), Cu₂O (460 mg, 3.21 mmol) and a solutionof prop-1-yne (212 mg, 5.29 mmol, 0.99 equiv) in pyridine (prepared at−78° C., 5 mL). The resulting solution was stirred for 1 h at 120° C.The resulting solution was diluted with ethyl acetate (10 mL). Theresulting solution was extracted with ethyl acetate (3×20 mL) and theorganic layers combined. The resulting mixture was washed with brine(3×30 mL). The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1/30-1/20) to yield5-iodo-2-methyl-1-benzofuran-7-carbaldehyde as a yellow solid.

b) 2-Methyl-5-(3-(methylthio)prop-1-yn-1-yl)benzofuran-7-carbaldehyde

Into a 50-mL sealed tube was placed5-iodo-2-methyl-1-benzofuran-7-carbaldehyde (1.2 g, 4.19 mmol),3-(methylsulfanyl)prop-1-yne (724 mg, 8.40 mmol), Pd(PPh₃)₂Cl₂ (147 mg,0.21 mmol), CuI (80 mg, 0.42 mmol), N,N-dimethylformamide (20 mL) andTEA (1.27 g, 12.55 mmol). The resulting solution was stirred overnightat 80° C. The reaction was then quenched by the addition of water (10mL). The resulting solution was extracted with ethyl acetate (3×20 mL)and the organic layers combined. The resulting mixture was washed withbrine (3×30 mL). The resulting mixture was concentrated under vacuum.The resulting residue was purified on a silica gel column with PE/EtOAc(30/1-20/1) to yield2-methyl-5-[3-(methylsulfanyl)prop-1-yn-1-yl]-1-benzofuran-7-carbaldehydeas yellow oil.

c) Ethyl3-(2,3-dimethyl-4-((2-methyl-5-(3-(methylthio)prop-1-yn-1-yl)benzofuran-7-yl)methoxy)phenyl)propanoate

The title compound was prepared by reduction of2-methyl-5-[3-(methylsulfanyl)prop-1-yn-1-yl]-1-benzofuran-7-carbaldehydealdehyde with LiAlH₄ and coupled to ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate according to the procedure inExample 20.

d) Ethyl3-(2,3-dimethyl-4-((2-methyl-5-(3-(methylthio)propyl)benzofuran-7-yl)methoxy)phenyl)propanoate

Into a 50-mL round bottom flask purged and maintained with an inertatmosphere of H₂ was placed ethyl3-[2,3-dimethyl-4-([2-methyl-5-[3-(methylsulfanyl)prop-1-yn-1-yl]-1-benzofuran-7-yl]methoxy)phenyl]propanoate(150 mg, 0.33 mmol), ethyl acetate (5 mL) and palladium on carbon (150mg). The resulting solution was stirred for 4 h at 25° C. The solidswere filtered out. The resulting mixture was concentrated under vacuumto yield ethyl3-[2,3-dimethyl-4-([2-methyl-5-[3-(methylsulfanyl)propyl]-1-benzofuran-7-yl]methoxy)phenyl]propanoateas yellow oil.

e)3-(2,3-Dimethyl-4-((2-methyl-5-(3-(methylthio)propyl)benzofuran-7-yl)methoxy)phenyl)propanoicacid

To a solution of ethyl3-[2,3-dimethyl-4-([2-methyl-5-[3-(methylsulfanyl)propyl]-1-benzofuran-7-yl]methoxy)phenyl]propanoate(130 mg, 0.29 mmol) in tetrahydrofuran (2 mL) was added a solution ofLiOH (130 mg, 5.43 mmol) in water (2 mL). The resulting solution wasstirred overnight at 25° C. The pH value of the solution was adjusted topH 5 with hydrogen chloride (2 mol/L). The resulting solution wasextracted with ethyl acetate (3×10 mL) and the organic layers combinedand dried over anhydrous sodium sulfate and concentrated under vacuum toyield3-[2,3-dimethyl-4-([2-methyl-5-[3-(methylsulfanyl)propyl]-1-benzofuran-7-yl]methoxy)phenyl]propanoicacid as yellow oil.

f)3-[2,3-Dimethyl-4-({2-methyl-5-[3-(methylsulfonyl)propyl]-1-benzofuran-7-yl}methoxy)phenyl]propanoicacid

Into a 50-mL round-bottom flask was placed3-[2,3-dimethyl-4-([2-methyl-5-[3-(methylsulfanyl)propyl]-1-benzofuran-7-yl]methoxy)phenyl]propanoicacid (100 mg, 0.23 mmol), dichloromethane (3 mL) and m-CPBA (80 mg, 0.46mmol). The resulting solution was stirred for 2 h at 25° C. Theresulting mixture was concentrated under vacuum. The resulting residuewas purified by RP-HPLC (C18) to yield3-(4-[[5-(3-methanesulfonylpropyl)-2-methyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a white solid.

¹H NMR: (300 MHz, CD₃OD) δ: 7.19 (s, 1H), 7.14 (s, 1H), 7.05 (s, 1H),6.84 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 5.17 (s,2H), 2.71-2.97 (m, 8H), 2.34-2.66 (m, 5H), 1.93-2.11 (m, 10H). Massspectrum (ESI, m/z): Calculated for C₂₅H₃₀O₆S, 481 (M+Na), found 481.

Example 623-{4-[(6-Chloro-2-methyl-1-benzothiophen-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 3-Bromo-5-chlorobenzenethiol

Into a 250-mL round-bottom flask was placed3-bromo-5-chlorobenzene-1-sulfonyl chloride (3.8 g, 13.11 mmol), PPh₃(12 g, 45.75 mmol), tetrahydrofuran (200 mL) and water (10 mL). Theresulting solution was stirred overnight at 50° C. The resultingsolution was diluted with sodium hydroxide (100 mL). The resultingmixture was washed with ethyl acetate (2×200 mL). The pH value of thesolution was adjusted to pH 3 with hydrogen chloride (6 mol/L). Theresulting solution was extracted with ethyl acetate (2×300 mL) and theorganic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum to yield 3-bromo-5-chlorobenzene-1-thiol asred oil.

b) Ethyl 2-((3-bromo-5-chlorophenyl)thio)propanoate

Into a 250-mL round-bottom flask was placed3-bromo-5-chlorobenzene-1-thiol (8.8 g, 39.37 mmol), ethyl2-bromopropanoate (21.4 g, 118.21 mmol), potassium carbonate (16.4 g,118.66 mmol), and acetone (100 mL). The resulting solution was stirredovernight at 60° C. The resulting solution was diluted with water (50mL). The resulting solution was extracted with ethyl acetate (3×50 mL)and the organic layers combined and dried over anhydrous sodium sulfate.The solids were filtered out. The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith ethyl acetate/petroleum ether (5/95). The collected fractions werecombined and concentrated under vacuum to yield ethyl2-((3-bromo-5-chlorophenyl)thio)propanoate as yellow oil.

c) 2-((3-Bromo-5-chlorophenyl)thio)propanal

To a solution of ethyl 2-[(3-bromo-5-chlorophenyl)sulfanyl]propanoate (2g, 6.18 mmol) in toluene (20 mL) was added DIBAL (6.2 mL, 1mol/L)dropwise with stirring at −78° C. The resulting solution was stirred for30 min at −78° C. The reaction was then quenched by the addition ofwater (20 mL). The solids were filtered out. The resulting solution wasextracted with ethyl acetate (4×20 mL) and the organic layers combinedand dried over anhydrous sodium sulfate. The solids were filtered out.The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (5/95). The collected fractions were combined and concentratedunder vacuum to yield 2-[(3-bromo-5-chlorophenyl)sulfanyl]propanal asyellow oil.

d) 4-Bromo-6-chloro-2-methylbenzo[b]thiophene

Into a 50-mL round-bottom flask was placed PPA (5 mL) and2-[(3-bromo-5-chlorophenyl)sulfanyl]propanal (1.2 g, 4.29 mmol) wasadded dropwise with stirring at 150° C. in 30 min. The resultingsolution was stirred for 30 min at 150° C. The reaction was thenquenched by the addition of water (20 mL). The resulting solution wasextracted with ethyl acetate (3×20 mL) and the organic layers combinedand dried over anhydrous sodium sulfate. The solids were filtered out.The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1/99). The collected fractions were combined and concentratedunder vacuum to yield 4-bromo-6-chloro-2-methyl-1-benzothiophene as awhite solid.

e)3-{4-[(6-Chloro-2-methyl-1-benzothiophen-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 57 substituting 4-bromo-6-chloro-2-methyl benzo[b]thiophenefor 7-bromo-5-chloro-2-methyl-1-benzothiophene in step (d).

¹H NMR: (300 MHz, CDCl₃) δ: 7.71 (s, 1H), 7.39 (s, 1H), 7.16 (s, 1H),6.99 (d, J=6.3 Hz, 1H), 6.75 (d, J=6.3 Hz, 1H), 5.11 (s, 2H), 2.98 (t,J=6 Hz, 2H), 2.60-2.64 (m, 5H), 2.26 (s,3H), 2.23 (s, 3H). Mass spectrum(ESI, m/z): Calculated for C₂₁H₂₁ClO₃S, 387 (M−H), found 387.

Example 633-{4-[(6-Chloro-2-methyl-1-benzothiophen-4-yl)methoxy]-3,5-difluorophenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 62 substituting ethyl3-(3,5-difluoro-4-hydroxyphenyl)propanoate for ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate.

¹H NMR: (300 MHz, CD₃OD) δ: 7.74 (s, 1H), 7.42 (s, 1H), 7.17 (s, 1H),6.91 (d, J=6.9 Hz, 2H), 5.18 (s, 2H), 2.88 (t, J=5.7 Hz, 2H), 2.57-2.62(m, 5H). Mass spectrum (ESI, m/z): Calculated for C₁₉H₁₅ClF₂O₃S, 395(M−H), found 395.

Example 643-{4-[(6-Chloro-2-methyl-1-benzothiophen-4-yl)methoxy]-3,5-difluorophenyl}propan-1-ol

The title compound was prepared by reacting3-{4-[(6-chloro-2-methyl-1-benzothiophen-4-yl)methoxy]-3,5-difluorophenyl}propanoicacid (prepared as described in Example 63) according to procedure inExample 59.

¹H NMR: (300 MHz, CD₃OD) δ: 7.74 (s, 1H), 7.41 (s, 1H), 7.17 (s, 1H),6.86 (d, J=7.2 Hz, 2H), 5.18 (s, 2H), 3.56 (t, J=4.5 Hz,2H), 2.62-2.66(m, 5H), 1.76-1.83 (m, 2H).

Example 653-{4-[(2-tert-Butyl-6-chloro-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 2-Amino-3-bromo-5-chlorobenzenethiol

The title compound was prepared according to the procedure as describedin Example 66 substituting 2-bromo-4-chloroaniline for2-bromo-4-fluoroaniline.

b) 4-Bromo-2-(tert-butyl)-6-chlorobenzo[d]thiazole

Into a 100-mL round-bottom flask was placed2-amino-3-bromo-5-chlorobenzene-1-thiol (400 mg, 1.68 mmol), NMP (10 mL)and 2,2-dimethylpropanoyl chloride (403 mg, 3.34 mmol). The resultingsolution was stirred for 1 h at 130° C. The reaction was then quenchedby the addition of water (10 mL). The resulting solution was extractedwith ethyl acetate (3×10 mL) of ethyl acetate and the organic layerscombined. The resulting mixture was washed with brine (3×20 mL). Theresulting mixture was concentrated under vacuum. The resulting residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1/30-1/10) to yield 4-bromo-2-tert-butyl-6-chloro-1,3-benzothiazole asyellow oil.

c) Methyl 2-tert-butyl-6-chloro-1,3-benzothiazole-4-carboxylate

Into a 100-mL round-bottom flask was placed4-bromo-2-tert-butyl-6-chloro-1,3-benzothiazole (150 mg, 0.49 mmol),methanol (10 mL), Pd(dppf)Cl₂ (72 mg, 0.10 mmol) and triethylamine (149mg, 1.47 mmol). CO (g) was introduced and the resulting solution wasstirred overnight at 60° C. The resulting mixture was concentrated undervacuum. The product was purified by TLC(PE/EtOAc=5/1), to yield methyl2-tert-butyl-6-chloro-1,3-benzothiazole-4-carboxylate as a solid.

d) (2-Tert-butyl-6-chloro-1,3-benzothiazol-4-yl)methanol

To a solution of methyl2-tert-butyl-6-chloro-1,3-benzothiazole-4-carboxylate (120 mg, 0.42mmol) in ether (2 mL) was added LAH (16 mg, 0.42 mmol) at 0° C. Theresulting solution was stirred for 30 min at 0° C. The reaction was thenquenched by addition of sodium sulfate.10H₂O (500 mg).

The solids were filtered out. The resulting residue was concentratedunder vacuum. Then the product was purified by preparative TLC plate(PE/EA=5/1) to yield(2-tert-butyl-6-chloro-1,3-benzothiazol-4-yl)methanol as yellow oil.

e)3-{4-[(2-tert-Butyl-6-chloro-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting(2-tert-butyl-6-chloro-1,3-benzothiazol-4-yl)methanol according to theprocedure as described in Example 20 step (j).

¹H NMR: (300 MHz, DMSO) δ: 8.21 (s, 1H), 7.59 (s, 1H), 6.94(d, J=8.4 Hz,1H), 6.88 (d, J=8.4 Hz, 1H), 5.48 (s, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.39(d, J=8.1 Hz, 1H), 2.15 (s, 6H), 1.47 (s, 9H). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₆ClNO₃S, 432 (M+H), found 431.

Example 663-{4-[(2-Ethyl-6-fluoro-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 4-Bromo-6-fluorobenzo[d]thiazol-2-amine

To a solution of 2-bromo-4-fluoroaniline (10 g, 52.63 mmol) and NH₄SCN(20 g) in acetic acid (80 mL) was added a solution of Br₂ (9.2 g, 57.57mmol) in acetic acid (20 mL) at 0-5° C. The resulting solution wasstirred for 2 h at 0° C. The resulting solution was diluted with water(200 mL). The pH of the solution was adjusted to pH 7-8 with sodiumhydroxide (10%) and the resulting residue collected by filtration toyield 4-bromo-6-fluoro-1,3-benzothiazol-2-amine as a yellow solid.

b) 4-Bromo-6-fluorobenzo[d]thiazole

Into a 500-mL round-bottom flask was placed4-bromo-6-fluoro-1,3-benzothiazol-2-amine (12.0 g, 48.57 mmol),1,4-dioxane (100 mL) and 3-methylbutyl nitrite (31 g, 264.63 mmol). Theresulting solution was stirred for 1 h at 60° C. The resulting mixturewas concentrated under vacuum and the residue was purified by silica gelcolumn chromatography to yield 4-bromo-6-fluoro-1,3-benzothiazole as ayellow solid.

c) 2-Amino-3-bromo-5-fluorobenzenethiol

Into a 100-mL round-bottom flask was placed4-bromo-6-fluoro-1,3-benzothiazole (2.0 g, 8.62 mmol), ethanol (20 mL)and NH₂NH₂.H₂O (1.7 g). The resulting solution was stirred for 2 h at80° C. The resulting mixture was concentrated under vacuum and theresidue was purified by silica gel column chromatography to yield2-amino-3-bromo-5-fluorobenzene-1-thiol as yellow oil.

d) 4-Bromo-2-ethyl-6-fluorobenzo[d]thiazole

Into a 100-mL round-bottom flask was placed2-amino-3-bromo-5-fluorobenzene-1-thiol (800 mg, 3.60 mmol), NMP (20 mL)and propanoyl chloride (667 mg, 7.21 mmol). The resulting solution wasstirred for 1.5 h at 130° C. The resulting solution was diluted withethyl acetate (100 mL). The resulting mixture was washed with brine(3×30 mL). The resulting residue was dried over anhydrous sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum and the residue was purified by silica gelcolumn chromatography to yield 4-bromo-2-ethyl-6-fluorobenzo[d]thiazoleas colorless oil.

e) Methyl 2-ethyl-6-fluorobenzo[d]thiazole-4-carboxylate

Into a 100-mL round-bottom flask was placed4-bromo-2-ethyl-6-fluorobenzo[d]thiazole (320 mg, 1.23 mmol), methanol(20 mL), TEA (373 mg, 3.69 mmol), and Pd(dppf)Cl₂ (135 mg). CO (g) wasintroduced and the resulting solution was stirred overnight at 60° C.The resulting mixture was concentrated under vacuum and the residue waspurified by silica gel chromatograph to yield of methyl2-ethyl-6-fluorobenzo[d]thiazole-4-carboxylate as a colorless oil.

f)3-{4-[(2-Ethyl-6-fluoro-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl2-ethyl-6-fluorobenzo[d]thiazole-4-carboxylate according to theprocedure as described in Example 1.

¹H NMR: (300 MHz, DMSO): 7.95 (dd, J₁=8.7 Hz, J₂=2.7 Hz, 1H), 7.40 (dd,J₁=9.9 Hz, J₂=2.7 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz,1H), 5.49 (s, 2H), 3.14 (q, J₁=15.0 Hz, J₂=7.5 Hz, 2H), 2.77 (t, J=7.2Hz, 2H), 2.40 (t, J=7.5 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H). Mass spectrum(ESI, m/z): Calculated for C₂₁ H₂₂FNO₃S, 388 (M+H), found 388.

Example 673-(4-{[6-chloro-2-(1-methylethyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) 4-Bromo-6-chloro-2-isopropylbenzo[d]thiazole

Into a 100-mL round-bottom flask was placed2-amino-3-bromo-5-chlorobenzene-1-thiol (400 mg, 1.68 mmol, prepared asdescribed in Example 65), NMP (10 mL) and 2-methylpropanoyl chloride(359 mg, 3.37 mmol). The resulting solution was stirred for 1 h at 130°C. The reaction was then quenched by the addition of water (10 mL). Theresulting solution was extracted with ethyl acetate (3×10 mL) and theorganic layers combined. The resulting mixture was washed with brine(3×20 mL). The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1/30-1/10) to yield4-bromo-6-chloro-2-isopropylbenzo[d]thiazole as a light yellow oil.

b)3-(4-{[6-chloro-2-(1-methylethyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting4-bromo-6-chloro-2-isopropylbenzo[d]thiazole according to the procedureas described in Example 65.

¹H NMR: (300 MHz, DMSO) δ: 8.21 (s, 1H), 7.58 (s, 1H), 6.94 (d, J=8.4Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 5.48 (s, 2H), 3.40-3.49 (m, 1H), 2.77(t, J=8.1 Hz, 2H), 2.40 (d, J=8.4 Hz, 1H), 2.16 (s, 6H), 1.42 (s, 3H),1.40 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₄ClNO₃S, 416(M−H), found 416.

Example 683-{4-[(2-tert-butyl-6-fluoro-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 4-Bromo-2-(tert-butyl)-6-fluorobenzo[d]thiazole

Into a 100-mL round-bottom flask was placed2-amino-3-bromo-5-fluorobenzene-1-thiol (800 mg, 3.60 mmol, prepared asdescribed in Example 66), NMP (10 mL) and 2, 2-dimethylpropanoylchloride (872 mg, 7.23 mmol). The resulting solution was stirred for 1.5h at 130° C. The resulting solution was diluted with ethyl acetate (100mL). The resulting mixture was washed with brine (3×30 mL). Theresulting residue was dried over anhydrous sodium sulfate. The solidswere filtered out. The resulting mixture was concentrated under vacuum.The resulting residue was purified onto a silica gel column with ethylacetate/petroleum ether (1:5) to yield4-bromo-2-tert-butyl-6-fluoro-1,3-benzothiazole as yellow oil.

b)3-{4-[(2-tert-butyl-6-fluoro-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting4-bromo-2-(tert-butyl)-6-fluorobenzo[d]thiazole according to theprocedure as described in Example 65.

¹H NMR: (300 MHz, DMSO) δ: 7.95 (dd, J₁=8.7 Hz, J₂=2.7 Hz, 1H), 7.42(dd, J₁=9.9 Hz, J₂=2.7 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.87 (d, J=8.4Hz, 1H), 5.49 (s, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.38 (t, J=7.5 Hz, 2H),2.16 (s, 6H), 1.47 (s, 9H). Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₆FNO₃S, 416 (M−H), found 416.

Example 693-[4-({5-Chloro-2-methyl-6-[3-(methylsulfonyl)propyl]-1-benzofuran-7-yl}methoxy)-2,3-dimethylphenyl]propanoicacid

a) Methyl5-chloro-2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)benzofuran-7-carboxylate

The title compound was prepared according to the procedure as describedin Example 20 substituting prop-1-yne for but-1-yne in step (d).

b) Methyl5-chloro-2-methyl-6-(3-((trimethylsilyl)oxy)prop-1-en-1-yl)benzofuran-7-carboxylate

A mixture of methyl5-chloro-2-methyl-6-[(trifluoromethane)sulfonyloxy]-1-benzofuran-7-carboxylate(1 g, 2.68 mmol), DMF (10 mL),trimethyl([[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy])silane(1.37 g, 5.35 mmol), Pd(OAc)₂ (60 mg, 0.27 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (220 mg, 0.54 mmol),K₃PO₄ (1.4 g, 6.60 mmol) and water(1 mL). The resulting solution wasstirred overnight at 70° C. The reaction was then quenched by theaddition of water (20 mL). The resulting solution was extracted withethyl acetate (3×30 mL) and the organic layers combined. The resultingmixture was washed with brine (3×50 mL). The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with PE/EtOAc (30/1-10/1) to yield methyl5-chloro-2-methyl-6-[(1E)-3-[(trimethylsilyl)oxy]prop-1-en-1-yl]-1-benzofuran-7-carboxylateas yellow oil.

c) Methyl5-chloro-6-(3-hydroxyprop-1-en-1-yl)-2-methylbenzofuran-7-carboxylate

Into a 100-mL round flask was placed methyl5-chloro-2-methyl-6-[(1E)-3-[(trimethylsilyl)oxy]prop-1-en-1-yl]-1-benzofuran-7-carboxylate(800 mg, 2.27 mmol), tetrahydrofuran (10 mL) and TBAF(1N) (5 mL). Theresulting solution was stirred for 4 h at 25° C. The resulting mixturewas concentrated under vacuum. The resulting residue was purified on asilica gel column with PE/EtOAc (30/1-5/1) to yield methyl5-chloro-6-[(1E)-3-hydroxyprop-1-en-1-yl]-2-methyl-1-benzofuran-7-carboxylateas a white solid.

d) Methyl5-chloro-2-methyl-6-(3-((methylsulfonyl)oxy)prop-1-en-1-yl)benzofuran-7-carboxylate

Into a 50-mL round flask was placed methyl5-chloro-6-[(1E)-3-hydroxyprop-1-en-1-yl]-2-methyl-1-benzofuran-7-carboxylate(100 mg, 0.36 mmol), dichloromethane (3 mL), triethylamine (108 mg, 1.07mmol) and MsCl (81 mg, 0.71 mmol). The resulting solution was stirredfor 2 h at 25° C. The reaction was then quenched by the addition ofwater (10 mL). The resulting solution was extracted with DCM (3×10 mL)and the organic layers combined. The resulting mixture was washed withbrine (3×30 mL). The resulting residue was dried over sodium sulfate andconcentrated under vacuum to methyl5-chloro-6-[(1E)-3-(methanesulfonyloxy)prop-1-en-1-yl]-2-methyl-1-benzofuran-7-carboxylateas yellow oil.

e) Methyl5-chloro-2-methyl-6-(3-(methylthio)prop-1-en-1-yl)benzofuran-7-carboxylate

Into a 50-mL round bottom flask, was placed methyl5-chloro-6-[(1E)-3-(methanesulfonyloxy)prop-1-en-1-yl]-2-methyl-1-benzofuran-7-carboxylate(80 mg, 0.22 mmol), N,N-dimethylformamide (2 mL), CH₃SNa (78 mg, 1.11mmol), Cs₂CO₃ (362 mg, 1.11 mmol). The resulting solution was stirredfor 1 h at 25° C. The reaction was then quenched by the addition ofwater (10 mL). The resulting solution was extracted with ethyl acetate(3×10 mL) and the organic layers combined. The resulting mixture waswashed with brine (3×20 mL). The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith PE/EtOAc (30/1-10/1) to yield methyl5-chloro-2-methyl-6-[(1E)-3-(methylsulfanyl)prop-1-en-1-yl]-1-benzofuran-7-carboxylateas brown oil.

f) Methyl5-chloro-2-methyl-6-(3-(methylthio)propyl)benzofuran-7-carboxylate

Into a 50-mL round bottom flask was placed methyl5-chloro-2-methyl-6-[(1E)-3-(methylsulfanyl)prop-1-en-1-yl]-1-benzofuran-7-carboxylate(40 mg, 0.13 mmol), tetrahydrofuran (2 mL) and palladium on carbon (40mg). Hydrogen (gas) was introduced and the mixture was stirred for 4 hat 25° C. The solids were filtered out. The resulting mixture wasconcentrated under vacuum to yield methyl5-chloro-2-methyl-6-[3-(methylsulfanyl)propyl]-1-benzofuran-7-carboxylateas colorless oil.

g)3-(4-((5-Chloro-2-ethyl-6-(3-(methylthio)propyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting methyl5-chloro-2-methyl-6-(3-(methylthio)propyl)benzofuran-7-carboxylate byLiAlH₄ reduction, coupling and hydrolysis according to the procedure asdescribed in Example 20.

h)3-[4-({5-Chloro-2-methyl-6-[3-(methylsulfonyl)propyl]-1-benzofuran-7-yl}methoxy)-2,3-dimethylphenyl]propanoicacid

Into a 25-mL round-bottom flask was placed3-[4-([5-chloro-2-methyl-6-[3-(methylsulfanyl)propyl]-1-benzofuran-7-yl]methoxy)-2,3-dimethylphenyl]propanoicacid (15 mg, 0.03 mmol), dichloromethane (1 mL) and m-CPBA (11 mg, 0.06mmol). The resulting solution was stirred for 2 h at 25° C. Theresulting mixture was concentrated under vacuum and purified byRP-C18-HPLC to yield3-(4-[[5-chloro-6-(3-methanesulfonylpropyl)-2-methyl-1-benzofuran-7-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a off-white solid.

¹H NMR: (300 MHz, CD₃OD) δ: 7.57 (s, 1H), 6.97-7.04 (m, 2H), 6.47 (s,1H), 5.35 (s, 2H), 3.09-3.20 (m, 4H), 2.86-2.95 (m, 5H), 2.43-2.54 (m,5H), 2.27 (s, 3H), 2.10-2.22 (m, 5H). Mass spectrum (ESI, m/z):Calculated for C₂₅H₂₉ClO₆S, 491 (M−H), found 491.

Example 703-{4-[(6-Chloro-2-ethyl-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) (6-Chloro-2-ethylbenzo[d]thiazol-4-yl)methanol

The title compound was prepared according to the procedure as describedin Example 65 step (b) substituting propanoyl chloride for2,2-dimethylpropanoyl chloride.

b)3-{4-[(6-Chloro-2-ethyl-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting6-chloro-2-ethylbenzo[d]thiazol-4-yl)methanol according to the procedureas described in Example 20 step (j).

¹H NMR: (300 MHz, DMSO) δ: 8.19 (s, 1H), 7.56 (s, 1H), 6.94 (d, J=8.1Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 5.48 (s, 2H), 3.12-3.19 (m, 2H), 2.77(t, J=8.1 Hz, 2H), 2.40 (t, J=8.1 Hz, 2H), 2.16 (s, 6H), 1.38 (t, J=7.5Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₂ClNO₃S, 404(M+H), found 404.

Example 713-(4-{[6-Chloro-2-(2-methylpropyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 65 substituting 3-methylbutanoyl chloride for2,2-dimethylpropanoyl chloride in step (b).

¹H NMR: (300 MHz, DMSO) δ: 8.19 (s, 1H), 7.57 (s, 1H), 6.31 (d, J=8.7Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 5.48 (s, 2H), 3.01 (d, J=6.9 Hz, 2H),2.77 (t, J=7.5 Hz, 2H), 2.39 (t, J=7.5 Hz, 2H), 2.14-2.17 (m, 7H), 1.00(s, 3H), 0.09 (s, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₆ClNO₃S, 432 (M+H), found 432.

Example 723-(4-{[6-Fluoro-2-(1-methylethyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) 4-Bromo-6-fluoro-2-isopropylbenzo[d]thiazole

Into a 50-mL round-bottom flask was placed2-amino-3-bromo-5-fluorobenzene-1-thiol (800 mg, 3.60 mmol, prepared asdescribed in Example 66), NMP (10 mL), and 2-methylpropanoyl chloride(771 mg, 7.24 mmol). The resulting solution was stirred for 1.5 h at130° C. The resulting solution was diluted with ethyl acteate (100 mL).The resulting mixture was washed with brine (3×30 mL). The resultingresidue was dried over anhydrous sodium sulfate. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1:5) to4-bromo-6-fluoro-2-(propan-2-yl)-1,3-benzothiazole as yellow oil.

b)3-(4-{[6-Fluoro-2-(1-methylethyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting4-bromo-6-fluoro-2-(propan-2-yl)-1,3-benzothiazole according to theprocedure as described in Example 65.

¹H NMR: (300 MHz, DMSO) δ: 7.95 (d, J=6.9 Hz, 1H), 7.41 (d, J=9.6 Hz,1H), 6.94 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 5.49 (s, 2H),3.48-3.39 (m, 1H), 2.80-2.72 (m, 2H), 2.50-2.37 (m, 2H), 2.16 (s, 6H),1.41 (d, J=6.3 Hz, 6H). Mass spectrum (ESI, m/z): Calculated forC₂₂H₂₄FNO₃S, 400 (M−H), found 400.

Example 733-[4-{[2-Methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2-(trifluoromethyl)phenyl]propanoicacid

a) Methyl 2-hydroxy-5-(trifluoromethoxy)benzoate

To a solution of 2-hydroxy-5-(trifluoromethoxy)benzoic acid (2.2 g, 9.90mmol) in dichloromethane (10 mL) and methanol (2 mL) at 0° C. was addedtms-diazomethane (2M) (5 mL) dropwise and the solution was stirred for 3h at 25° C. The reaction was then quenched by the addition of water. Theresulting solution was extracted with DCM (3×10 mL) and the organiclayers combined and concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether(10/90). The collected fractions were combined and concentrated undervacuum to yield methyl 2-hydroxy-5-(trifluoromethoxy)benzoate ascolorless oil.

b) Methyl 3-bromo-2-hydroxy-5-(trifluoromethoxy)benzoate

Into a 50-mL round-bottom flask was placed methyl2-hydroxy-5-(trifluoromethoxy)benzoate (1 g, 4.23 mmol), CH₃CN (20 mL)and NBS (1.5 g, 8.43 mmol). The resulting solution was stirred overnightat 75° C. in an oil bath. The resulting mixture was concentrated undervacuum. The resulting residue was purified on a silica gel column withethyl acetate/petroleum ether (2/98). The collected fractions werecombined and concentrated under vacuum to yield methyl3-bromo-2-hydroxy-5-(trifluoromethoxy)benzoate as yellow oil.

c) Methyl 2-methyl-5-(trifluoromethoxy)benzofuran-7-carboxylate

Into a 50-mL pressure tank reactor was placed methyl3-bromo-2-hydroxy-5-(trifluoromethoxy)benzoate (1.2 g, 3.81 mmol),prop-1-yne (300 mg, 7.49 mmol), Pd(PPh₃)₂Cl₂ (268 mg, 0.38 mmol), CuI(73 mg, 0.38 mmol), triethylamine (760 mg, 7.51 mmol) andN,N-dimethylformamide (10 mL). The resulting solution was stirredovernight at 75° C. in an oil bath. The resulting solution was dilutedwith water. The resulting solution was extracted with ethyl acetate(3×15 mL) and the organic layers combined. The resulting mixture waswashed with water (2×15 mL). The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith ethyl acetate/petroleum ether (10/90). The collected fractions werecombined and concentrated under vacuum to yield methyl2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-carboxylate as a yellowsolid.

d) Ethyl 3-(4-hydroxy-2-(trifluoromethyl)phenyl)propanoate

The title compound was prepared according to the procedure as describedin Example 86 substituting 4-bromo-3-(trifluoromethyl)phenol for4-bromo-2,3-difluorophenol in step (a).

e)3-[4-{[2-Methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2-(trifluoromethyl)phenyl]propanoicacid

The title compound was prepared by reacting methyl2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-carboxylate and ethyl3-(4-hydroxy-2-(trifluoromethyl)phenyl)propanoate according to theprocedure as described in Example 1.

¹H NMR: (300 MHz, CD3OD) δ: 7.52-7.24 (m, 5H), 6.58 (s, 1H), 5.42 (s,2H), 3.04 (t, J=7.2 Hz, 2H), 2.57 (t, J=7.5 Hz, 2H), 2.51 (s, 3H). Massspectrum (ESI, m/z): Calculated for C₂₁H₁₆F₆O₅, 461 (M−H), found 461.

Example 743-(4-((5-cyano-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

Step A: Ethyl3-(4-((5-bromo-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

Ethyl3-(4-((5-bromo-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoatewas prepared according to the procedure as described in Example 83,substituting methyl 5-bromo-2-ethylbenzofuran-7-carboxylate (prepared asdescribed in Example 101, step (a)) for methyl2-ethyl-5-fluorobenzofuran-7-carboxylate in step (c).

Step B: Ethyl3-(4-((5-cyano-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

A mixture of ethyl3-(4-((5-bromo-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(300 mg, 0.65 mmol), zinc cyanide (77 mg, 0.65 mmol) and Pd(PPh₃)₄ (75mg, 0.065 mmol) in NMP (6 mL) was heated to 120° C. for 75 min in amicrowave reactor. The mixture was cooled to room temperature anddiluted with EtOAc. The EtOAc solution was washed with water, and brineand dried over Na₂SO₄. EtOAc was removed under vacuum and the resultingresidue was purified by silica gel column chromatography to yield ethyl3-(4-((5-cyano-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate.

Step C:3-(4-((5-Cyano-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

3-(4-((5-Cyano-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid was prepared from ethyl3-(4-((5-cyano-2-ethylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoateby hydrolysis with sodium hydroxide according to the procedure asdescribed in Example 86 step (e).

¹H NMR (CHLOROFORM-d) δ: 7.77 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H),6.99 (d, J=8.3 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.48 (s, 1H), 5.33 (s,2H), 2.91-3.00 (m, 2H), 2.80-2.90 (m, 2H), 2.58-2.65 (m, 2H), 2.26 (s,6H), 1.36 (t, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₃NO₄, 777.3(M2+Na), found 777.3.

Example 753-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-methylpyridin-3-yl)propanoicacid

Step A: Ethyl 3-(6-fluoro-2-methylpyridin-3-yl)propanoate

Ethyl 3-(6-fluoro-2-methylpyridin-3-yl)propanoate was prepared accordingto the procedure described in Example 86 steps (a and b) substituting3-bromo-6-fluoro-2-methylpyridine for 4-bromo-2,3-difluorophenol.

Step B:3-(6-((2-Ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-methylpyridin-3-yl)propanoicacid

3-(6-((2-Ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-methylpyridin-3-yl)propanoicacid was prepared from ethyl 3-(6-fluoro-2-methylpyridin-3-yl)propanoateand (2-ethyl-5-fluorobenzofuran-7-yl)methanol (prepared as describedExample 83 (c)) according to the procedure as described in Example 96.

¹H NMR (MeOD) δ: 7.49 (d, J=8.6 Hz, 1H), 7.13 (dd, J=8.6, 2.5 Hz, 1H),7.05 (dd, J=10.1, 2.5 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 6.48 (s, 1H),5.56 (s, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.78-2.85 (m, 2H), 2.52-2.58 (m,2H), 2.45 (s, 3H), 1.34 (t, 3H). Mass spectrum (ESI, m/z): Calcd. forC₂₀H₂₀FNO₄, 358.1 (M+H), found 358.0.

Example 763-(4-{[6-Fluoro-2-(2-methylpropyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 68 substituting 3-methylbutanoyl chloride for2,2-dimethylpropanoyl chloride.

¹H NMR: (300 MHz, DMSO) δ: 7.96 (dd, J=6.3 Hz, 2.1 Hz, 1H), 7.42 (dd,J=7.5 Hz, 1.8 Hz, 1H), 6.94 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.3 Hz, 1H),5.51 (s, 2H), 3.02 (d, J=6.4 Hz, 2H), 2.78 (t, J=6.3 Hz, 2H), 2.41 (t,J=6.0 Hz, 2H), 2.21-2.11 (m, 7H), 1.01 (s, 6H). Mass spectrum (ESI,m/z): Calculated for C₂₃H₂₆FNO₃S, 414 (M−H), found 414.

Example 773-(4-((5-Chloro-2-(2-fluorovinyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid (Mixture of E/Z)

3-(4-((5-Chloro-2-(2-fluorovinyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid (mixture of E/Z) was prepared according to the procedure asdescribed in Example 116 using ethyl3-(4-((5-chloro-2-(2-fluorovinyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(prepared as described in Example 112).

¹H NMR (CHLOROFORM-d) δ: 7.27-7.56 (m, 3H), 6.49-7.03 (m, 3H), 5.69-6.39(m, 1H), 5.22-5.32 (m, 2H), 2.87-3.03 (m, 2H), 2.61 (t, J=7.8 Hz, 2H),2.18-2.30 (m, 6H).

Example 783-(4-{[6-Fluoro-2-(trifluoromethyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) 4-Bromo-6-fluoro-2-(trifluoromethyl)benzo[d]thiazole

Into a 100-mL round-bottom flask was placed2-amino-3-bromo-5-fluorobenzene-1-thiol (800 mg, 3.60 mmol, prepared asdescribed in Example 66), NMP (10 mL) and trifluoroacetyl2,2,2-trifluoroacetate (1.5 g, 7.14 mmol). The resulting solution wasstirred for 1.5 h at 130° C. The resulting solution was diluted withethyl acetate (100 mL). The resulting mixture was washed with brine(3×30 mL). The resulting residue was dried over anhydrous sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:10) to yield4-bromo-6-fluoro-2-(trifluoromethyl)-1,3-benzothiazole as yellow oil.

b) Methyl 6-fluoro-2-(trifluoromethyl)benzo[d]thiazole-4-carboxylate

Into a 100-mL round-bottom flask was placed4-bromo-6-fluoro-2-(trifluoromethyl)-1,3-benzothiazole (300 mg, 1.00mmol), methanol (20 mL), TEA (303 mg, 2.99 mmol), and Pd(dppf)Cl₂ (110mg, 0.15 mmol). CO(g) was introduced and the mixture was stirredovernight at 60° C. The resulting mixture was concentrated under vacuum.The resulting residue was purified on a silica gel column with ethylacetate/petroleum ether (1:5) to yield methyl6-fluoro-2-(trifluoromethyl)-1,3-benzothiazole-4-carboxylate as yellowoil.

c)(6-Fluoro-2-(trifluoromethyl)-2,3-dihydrobenzo[d]thiazol-4-yl)methanol

The title compound was prepared by reacting methyl6-fluoro-2-(trifluoromethyl)benzo[d]thiazole-4-carboxylate using LiAlH₄reduction according to the procedure as described in Example 1.

d) (6-Fluoro-2-(trifluoromethyl)benzo[d]thiazol-4-yl)methanol

Into a 25-mL round-bottom flask was placed[6-fluoro-2-(trifluoromethyl)-2,3-dihydro-1,3-benzothiazol-4-yl]methanol(100 mg, 0.39 mmol), dichloromethane (10 mL), andtetrachlorocyclohexa-2,5-diene-1,4-dione (194 mg, 0.79 mmol). Theresulting solution was stirred for 30 min at 25° C. The resultingmixture was concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/hexane (1:4) to yield[6-fluoro-2-(trifluoromethyl)-1,3-benzothiazol-4-yl]methanol as yellowoil.

e) Tert-butyl3-(4-((6-fluoro-2-(trifluoromethyl)benzo[d]thiazol-4-yl)methoxy)-2,3-dimethylphenyl)propanoate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed[6-fluoro-2-(trifluoromethyl)-1,3-benzothiazol-4-yl]methanol (40 mg,0.16 mmol), tert-butyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (60mg, 0.24 mmol, prepared as described in Example 26), ADDP (87 mg, 0.35mmol), Bu₃P (48 mg) and toluene (10 mL). The resulting solution wasstirred overnight at 60° C. The resulting mixture was concentrated undervacuum. The resulting residue was purified on a silica gel column withethyl acetate/petroleum ether (1:10) to yield tert-butyl3-(4-[[6-fluoro-2-(trifluoromethyl)-1,3-benzothiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoateas a white solid.

f)3-(4-{[6-Fluoro-2-(trifluoromethyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

Into a 25-mL round-bottom flask was placed tert-butyl3-(4-[[6-fluoro-2-(trifluoromethyl)-1,3-benzothiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoate(50 mg, 0.10 mmol), dichloromethane (10 mL) and trifluoroacetic acid (2mL). The resulting solution was stirred overnight at 25° C. Theresulting solution was diluted with DCM (10 mL). The resulting mixturewas washed with brine (3×5 mL). The resulting residue was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum to yield3-(4-[[6-fluoro-2-(trifluoromethyl)-1,3-benzothiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoicacid as a off-white solid.

¹H NMR: (400 MHz, DMSO) δ: 7.95 (dd, J=8.4 Hz, 2.8 Hz, 1H), 7.42 (dd,J=9.6 Hz, 2.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H),5.58 (s, 2H), 2.77 (t, J=8.4 Hz, 2H), 2.41 (t, J=8.4 Hz, 2H), 2.18 (s,3H), 2.17 (s, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₀H₁₇F₄NO₃S, 426 (M−H), found 426.

Example 793-(4-{[6-Chloro-2-(trifluoromethyl)-1,3-benzothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 78 substituting 2-amino-3-bromo-5-chlorobenzene-1-thiol(prepared as described in Example 65) for2-amino-3-bromo-5-fluorobenzene-1-thiol.

¹H NMR: (300 MHz, DMSO) δ: 8.51 (s, 1H), 7.81 (s, 1H), 6.86-6.97 (m,2H), 5.55 (s, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.40 (d, J=7.2 Hz, 1H), 2.16(s, 6H). Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₇ClF₃NO₃S, 442(M−H), found 442.

Example 803-{4-[(5-Chloro-2-methyl-1,3-benzothiazol-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Ethyl 2,5-dichloro-3-nitrobenzoate

Into a 100-mL round-bottom flask was placed 2,5-dichloro-3-nitrobenzoicacid (1 g, 4.24 mmol), potassium carbonate (2.34 g, 16.93 mmol),acetone, and diethyl sulfate (1.6 g, 10.38 mmol). The resulting solutionwas stirred for 1 hat 55° C. The resulting mixture was concentratedunder vacuum. The resulting residue was purified on a silica gel columnwith ethyl acetate/petroleum ether (1:10) to yield ethyl2,5-dichloro-3-nitrobenzoate as colorless oil.

b) Ethyl 2-(benzylthio)-5-chloro-3-nitrobenzoate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed ethyl 2,5-dichloro-3-nitrobenzoate(1.1 g, 4.17 mmol), N,N-dimethylformamide (20 mL), potassium carbonate(1.73 g, 12.52 mmol) and phenylmethanethiol (570 mg, 4.59 mmol). Theresulting solution was stirred for 6 h at 90° C. The resulting solutionwas diluted with ethyl acetate (100 mL). The resulting mixture waswashed with brine (3×30 mL). The resulting residue was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The resulting residue waspurified on a silica gel column with ethyl acetate/petroleum ether (1:5)to yield ethyl 2-(benzylsulfanyl)-5-chloro-3-nitrobenzoate as a solid.

c) Ethyl 3-amino-2-(benzylthio)-5-chlorobenzoate

Into a 100-mL round-bottom flask was placed ethyl2-(benzylsulfanyl)-5-chloro-3-nitrobenzoate (1.2 g, 3.41 mmol), ethanol(30 mL), Fe (1.9 g) and NH4Cl (ac) (10 mL). The resulting mixture wasstirred for 6 h at 60° C. The resulting mixture was concentrated undervacuum. The resulting solution was diluted with ethyl acetate (100 mL).The resulting residue was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The resulting residue was purified on a silica gel column withethyl acetate/petroleum ether (1:3) to yield ethyl3-amino-2-(benzylthio)-5-chlorobenzoate as yellow oil.

d) 3-Amino-5-chloro-2-mercaptobenzoic acid

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed ethyl3-amino-2-(benzylsulfanyl)-5-chlorobenzoate (800 mg, 2.49 mmol), tot (30mL) and AlCl₃ (1.32 g). The resulting solution was stirred overnight at30° C. The resulting mixture was concentrated under vacuum. Theresulting residue was purified on a silica gel column withdichloromethane/methanol (10:1) to yield3-amino-5-chloro-2-mercaptobenzoic acid as a yellow solid.

e) 5-Chloro-2-methylbenzo[d]thiazole-7-carboxylic acid

Into a 100-mL round-bottom flask was placed3-amino-5-chloro-2-mercaptobenzoic acid (600 mg, 2.76 mmol), NMP (10 mL)and acetyl chloride (433 mg, 5.52 mmol). The resulting solution wasstirred for 2 hat 130° C. The resulting solution was diluted with ethylacetate (100 mL). The resulting mixture was washed with brine (3×30 mL).The resulting residue was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum to yield 5-chloro-2-methyl-1,3-benzothiazole-7-carboxylic acid asyellow oil.

f) (5-Chloro-2-methylbenzo[d]thiazol-7-yl)methanol

To a solution of 5-chloro-2-methyl-1,3-benzothiazole-7-carboxylic acid(380 mg, 1.67 mmol) in diethyl ether (20 mL) was added LiAlH₄ (127 mg,3.35 mmol) at 0-5° C. The resulting solution was stirred for 30 min at0° C. The reaction was then quenched by the addition of water (1 mL).The resulting mixture was concentrated under vacuum. The resultingresidue was purified on a silica gel column with ethyl acetate/petroleumether (1:2) to yield (5-chloro-2-methyl-1,3-benzothiazol-7-yl)methanolas a yellow solid.

g)3-{4-[(5-Chloro-2-methyl-1,3-benzothiazol-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting(5-chloro-2-methyl-1,3-benzothiazol-7-yl)methanol according to theprocedure as described in Example 1.

¹H NMR (DMSO-d₆) δ: 12.08 (s, 1H), 7.99 (d, J=1.7 Hz, 1H), 7.64 (d,J=1.5 Hz, 1H), 6.90-6.99 (m, 1H), 6.78-6.87 (m, 1H), 5.31 (s, 2H), 2.82(s, 3H), 2.73-2.81 (m, 2H), 2.40 (t, J=7.8 Hz, 2H), 2.19 (s, 3H), 2.17(s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₀1H₂₀ClNO₃S, 388(M−H), found 388.

Example 813-(4-((5-chloro-2-methyl-2H-indazol-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

a) 5-chloro-2-methyl-2H-indazole-7-carbaldehyde and5-chloro-1-methyl-1H-indazole-7-carbaldehyde

A solution of commercially available 5-chloro-1H-indazole-7-carbaldehyde(344 mg, 1.90 mmol) in dry DMF (5 mL) was added carefully to asuspension of NaH (56 mg, 2.22 mmol) in dry DMF (15 mL) and stirred for30 minutes at ambient temperature. Methyl iodide (140 μL, 2.25 mmol) wasadded and the reaction mixture stirred overnight. The next day, thesolution was cautiously poured onto water and extracted with diethylether. Washing of the organic layer with brine, followed byconcentration in vacuo and purification of the residue by flashchromatography (SiO₂, 10-100% dcm/heptanes) yielded the title mixture ofisomers (ca. 60:40 based on integration of the aldehyde NMR signals) asa residue, which was used in the next step without further separation.

b) (5-Chloro-2-methyl-2H-indazol-7-yl)methanol and(5-chloro-1-methyl-1H-indazol-7-yl)methanol.

The residue prepared in step (a) above (368 mg, 1.89 mmol) was dissolvedin dry THF (12 mL) and treated with a solution of lithiumaluminum-tri-tert-butoxyhydride (2.50 mL, 2.50 mmol, 1 M in THF) underargon. After stirring the resulting mixture at room temperature for 4 h,a saturated solution of sodium tartrate was added and the resultingmixture stirred at room temperature. The resulting mixture was extractedwith diethyl ether, then concentrated in vacuo and purified of theresidue by flash chromatography (SiO₂, step gradient: DCM→10% diethylether/DCM→diethyl ether) to yield the title compounds, as separatedresidues.

(5-chloro-2-methyl-2H-indazol-7-yl)methanol: ¹H NMR (MeOD) δ: 8.14 (s,1H), 7.57 (s, 1H), 7.28 (s, 1H), 4.97 (s, 2H), 4.19 (s, 3H).

(5-chloro-1-methyl-1H-indazol-7-yl)methanol: ¹H NMR (MeOD) δ: 7.94 (s,1H), 7.68 (s, 1H), 7.32 (s, 1H), 4.97 (s, 2H), 4.32 (s, 3H).

c) Ethyl3-(4-((5-chloro-2-methyl-2H-indazol-7-yl)methoxy)-2,3-dimethylphenyl)-propanoate

Into a 40 mL vial equipped with a septum cap and stirbar was placed(5-chloro-2-methyl-2H-indazol-7-yl)methanol (28.8 mg, 0.146 mmol), ethyl3-(4-hydroxy-2,3-dimethylphenyl)-propanoate (69.4 mg, 0.312 mmol),triphenylphosphine (88 mg, 0.336 mmol) and dry THF (12 mL). The vial wascooled to 0° C. under argon and treated dropwise withdiisopropylazodicarboxylate (70 μL, 0.338 mmol). The resulting mixturewas allowed to warm to room temperature overnight, then concentrated invacuo. The resulting residue was purified by by flash chromatography(SiO₂, 50% ether/heptane) to yield the title compound as a residue.

¹H NMR (CHLOROFORM-d) δ: 7.87 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 6.95(d, J=8.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 5.46 (s, 2H), 4.18-4.26 (m,3H), 4.14 (q, J=7.1 Hz, 2H), 2.85-2.97 (m, 2H), 2.53 (t, J=8.1 Hz, 2H),2.31 (s, 3H), 2.26 (s, 3H), 1.25 (t, J=7.1 Hz, 3H).

d)3-(4-((5-Chloro-2-methyl-2H-indazol-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

Into a 20 mL scintillation vial was placed ethyl3-(4-((5-chloro-2-methyl-2H-indazol-7-yl)methoxy)-2,3-dimethylphenyl)-propanoate(16 mg, 0.0399 mmol) followed by potassium hydroxide (100 μL, 0.25 mmol,2.5 M aqueous), THF (10 mL) methanol (2 mL) and water (2 mL). Theresulting mixture was stirred overnight at ambient temperature and thenthe pH was adjusted to pH˜4 by the addition of aqueous HCl. Theresulting mixture was extracted with ethyl acetate, the organic layerwas dried (MgSO₄) and then concentrated in vacuo to yield the titlecompound as a white solid.

¹H NMR (ACETONITRILE-d₃) δ: 8.10 and 8.05 (s, 1H), 7.65-7.69 and7.56-7.63 (s, 1H), 7.29-7.33 and 7.20 (s, 1H), 6.91-6.99 (m, 1H),6.78-6.86 (m, 1H), 5.44-5.48 and 5.38-5.44 (m, 2H), 4.17-4.20 and4.12-4.17 (m, 3H), 2.81-2.89 (m, 2H), 2.46-2.53 (m, 2H), 2.22 (s, 3H)Note: other methyl group buried under water peak.

Example 823-(4-((5-chloro-1-methyl-1H-indazol-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

a) Ethyl3-(4-((5-chloro-1-methyl-1H-indazol-7-yl)methoxy)-2,3-dimethylphenyl)-propanoate

Into a 40 mL vial equipped with a septum cap and stirbar was placed(5-chloro-1-methyl-1H-indazol-7-yl)methanol (76 mg, 0.387 mmol, preparedas described in Example 81 step b), ethyl3-(4-hydroxy-2,3-dimethylphenyl)-propanoate (86 mg, 0.389 mmol),triphenylphosphine (107 mg, 0.408 mmol) and dry THF (12 mL). The vialwas cooled to 0° C. under argon and treated dropwise withdiisopropylazodicarboxylate (80 μL, 0.386 mmol). The resulting mixturewas allowed to warm to room temperature overnight, then concentrated invacuo. The resulting residue was purified flash chromatography (SiO₂,50% ether/heptane) to yield the title compound as a residue.

¹H NMR (CHLOROFORM-d) δ: 7.94 (s, 1H), 7.70 (s, 1H), 7.34 (s, 1H), 7.03(d, J=8.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 5.26 (s, 2H), 4.22 (s, 3H),4.15 (q, J=7.1 Hz, 2H), 2.95 (t, J=7.9 Hz, 2H), 2.55 (t, J=7.9 Hz, 2H),2.23 (s, 3H), 2.12 (s, 3H), 1.26 (t, 3H).

b)3-(4-((5-chloro-1-methyl-1H-indazol-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

Into a 20 mL vial was placed ethyl3-(4-((5-chloro-1-methyl-1H-indazol-7-yl)methoxy)-2,3-dimethylphenyl)-propanoate(70 mg, 0.175 mmol) followed by potassium hydroxide (300 μL, 0.75 mmol,2.5 M aqueous), THF (10 mL) methanol (2 mL) and water (2 mL). Theresulting mixture was stirred overnight at ambient temperature and thenthe pH was adjusted to pH -4 by the addition of aqueous HCl. Theresulting mixture was extracted with ethyl acetate, the organic layerwas dried (MgSO₄) and concentration in vacuo to yield the title compoundas a white solid.

¹H NMR (ACETONITRILE-d₃) δ: 7.96 (s, 1H), 7.77 (s, 1H), 7.42 (s, 1H),6.98-7.08 (m, 1H), 6.86-6.95 (m, 1H), 5.39 (s, 2H), 4.19 (s, 3H),2.83-2.92 (m, 2H), 2.46-2.55 (m, 2H), 2.20 (s, 3H), 2.09 (s, 3H).

Example 833-(4-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

a) Methyl 3-bromo-5-fluoro-2-hydroxybenzoate

A 1-L round bottom flask was charged with methyl5-fluoro-2-hydroxybenzoate (9.40 g, 55.25 mmol) and methanol (320 mL). Asolution of bromine (3.21 mL, 62.43 mmol) and methanol (140 mL) wasadded dropwise via an addition funnel. The resulting mixture was stirredat room temperature overnight. The resulting mixture was concentrated invacuo and purified using the Analogix IF-280, 400 g column, 95:5Heptane:EtOAc to yield Methyl 3-bromo-5-fluoro-2-hydroxybenzoate.

¹H NMR (CHLOROFORM-d) δ: 7.17-7.22 (m, 1H), 6.93-6.96 (m, 1H), and 3.49(s, 3H).

b) Methyl 2-ethyl-5-fluorobenzofuran-7-carboxylate

A 20 mL sealed tube was charged with methyl3-bromo-5-fluoro-2-hydroxybenzoate (1.39 g, 4.01 mmol) and DMF (4.0 mL).The resulting mixture was cooled using a dry ice and acetone bath to−78° C. To the resulting mixture was then bubbled 1-butyne for 10minutes. To the resulting mixture was then added copper iodide (76.5 mg,0.402 mmol) and Pd(PPh₃)₂Cl₂ (281.8 mg, 0.402 mmol). The resultingmixture was flushed with argon, the tube was sealed and the mixturestirred at room temperature for 1 h, then heated to 75° C. and stirovernight. The resulting mixture was concentrated in vacuo and purifiedusing the Analogix IF-280, 150g column, 95:5-90:10 Heptane:EtOAc toyield methyl 2-ethyl-5-fluorobenzofuran-7-carboxylate.

¹H NMR (CHLOROFORM-d) 7.52-7.58 (m, 1H), 7.28-7.34 (m, 1H), 6.40 (s,1H), 3.89 (s, 3H), 2.82 (q, J=7.8 Hz, J=11.7 Hz, 2H) and 1.35 (t, J=7.8Hz, 3H).

c) (2-ethyl-5-fluorobenzofuran-7-yl)methanol

A 20 mL vial was charged with methyl2-ethyl-5-fluorobenzofuran-7-carboxylate (200 mg, 0.90 mmol) and 2.4 mLof dichloromethane. The resulting mixture was cooled using a dry ice andacetone bath to −78° C. To the resulting mixture was then added dropwisevia syringe a dichloromethane solution of DIBAL (3.60 mL, 3.60 mmol).The resulting mixture was warmed to room temperature over 20 minutes.The resulting mixture was poured into aqueous sodium hydroxide solution(50 mL). The layers were separated and the aqueous layer extracted threemore times with ethyl acetate (100 mL each time). The organic layerswere dried with magnesium sulfate, filtered through CELITE andconcentrate in vacuo to yield (2-ethyl-5-fluorobenzofuran-7-yl)methanol,which was used without further purification.

¹H NMR (CHLOROFORM-d) δ: 7.04-7.08 (m, 1H), 6.95-7.02 (m, 1H), 6.35 (s,1H), 4.94-4.99 (m, 2H), 2.80 (q, J=7.8 Hz, J=11.7 Hz, 2H) and 1.33 (t,J=7.8 Hz, 3H).

d) Ethyl3-(4-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

A 10 mL round bottom flask was charged with ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (389.0 mg, 1.79 mmol),(2-ethyl-5-fluorobenzofuran-7-yl)methanol (174.0 mg, 0.896 mmol),triphenylphosphine (367.0 mg, 1.40 mmol) and tetrahydrofuran (1.26 mL).The resulting mixture was cooled using an ice/water bath. to theresulting mixture was then added a 40% wt solution of diethylazodicarboxylate (0.66 mL, 1.44 mmol) was added dropwise. The resultingmixture was allowed to warm to room temperature with stirring overnight.The resulting mixture was concentrated in vacuo and purified using theAnalogix IF-280, 40 g column, 95:5-90:10 Heptane:EtOAc to yield ethyl3-(4-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate.

¹H NMR (CHLOROFORM-d) δ: 7.02-7.13 (m, 2H), 6.91-7.00 (m, 1H), 6.73-6.82(m, 1H), 6.35 (s, 1H), 5.28 (s, 2H), 4.13 (q, J=7.8 Hz, J=11.7 Hz, 2H),2.87-2.96 (m, 2H), 2.80 (q, J=7.8 Hz, J=11.7 Hz, 2H), 2.47-2.56 (m, 2H),2.25 (s, 3H), 2.23 (s, 3H), 1.33 (t, J=7.8 Hz, 3H) and 1.24 (t, J=7.8Hz, 3H).

e)3-(4-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

A 10 mL round bottom flask was charged with ethyl3-(4-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(243.5 mg, 0.611 mmol), tetrahydrofuran (5.1 mL), water (2.1 mL), andlithium hydroxide (256.4 mg, 6.11 mmol). The resulting mixture wasstirred at room temperature overnight. The resulting mixture was thenwashed with diethyl ether. The resulting residue was then acidified with2N HCl. The resulting mixture was extracted with ethyl acetate (2×100mL). The organic layers were dried with magnesium sulfate, filter andconcentrate in vacuo. The resulting residue was purified using theAnalogix IF-280, 40 g column, 90:10-50:50 Heptane:EtOAc to yield3-(4-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid.

¹H NMR (CHLOROFORM-d) δ: 7.06-7.14 (m, 2H), 6.96-7.02 (m, 1H), 6.77-6.83(m, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 2.90-3.00 (m, 2H), 2.80 (q, J=7.8Hz, J=11.7 Hz, 2H), 2.56-2.65 (m, 2H), 2.26 (s, 3H), 2.25 (s, 3H), and1.37 (t, J=7.8 Hz, 3H); LC/MS (ES+) m/z 371 (M+1).

Example 843-(4-((5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

a) Methyl 5-fluoro-2-(trifluoromethyl)benzofuran-7-carboxylate

A 20 mL sealed tube was charged with methyl3-bromo-5-fluoro-2-hydroxybenzoate (1.39 g, 4.01 mmol, prepared asdescribed in Example 83) and 4.0 mL of dimethylformamide. The resultingmixture was cooled using a dry ice and acetone bath to −78° C. Inot theresulting mixture was then bubbled 3,3,3-trifluoroprop-1-yne for 10minutes; followed by addition of copper iodide (76.5 mg, 0.402 mmol) andPd(PPh₃)₂Cl₂ (281.8 mg, 0.402 mmol). The reaction mixture was flushedwith argon, the tube sealed and the resulting mixture stirred at roomtemperature for 1 h, then heated to 75° C. and stirred overnight. Theresulting mixture was concentrated in vacuo and the resulting residueusing the Analogix IF-280, 150 g column, 95:5-90:10 Heptane:EtOAc toyield methyl 5-fluoro-2-(trifluoromethyl)benzofuran-7-carboxylate, whichwas used directly in the next step.

b) (5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methanol

A 50 mL round bottom flask was charged with methyl5-fluoro-2-(trifluoromethyl)benzofuran-7-carboxylate (1.05 g, 4.00 mmol)and 10.5 mL of dichloromethane. The resulting mixture was cooled using adry ice and acetone bath to −78° C. To the resulting mixture was thenadded dropwise via syringe a dichloromethane solution of DIBAL (16.0 mL,16.0 mmol). The resulting mixture was warmed to room temperature over 20minutes, then poured into aqueous sodium hydroxide solution (50 mL). Thelayers were separated, and the aqueous layer extracted three more timeswith ethyl acetate (100 mL each time). The organic layers were driedwith magnesium sulfate, filtered through CELITE and concentrated invacuo to yield (5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methanol,which was used without further purification.

¹H NMR (CHLOROFORM-d) δ: 7.56-7.61 (m, 1H), 7.51-7.55 (m, 1H), 6.30-6.36(m, 1H), and 4.94-5.03 (m, 2H).

c) Ethyl3-(4-((5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

A 10 mL round bottom flask was charged with ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (1.71 g, 7.69 mmol),(5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methanol (900.0 mg, 3.84mmol), triphenylphosphine (1.57 g, 6.00 mmol) and tetrahydrofuran (5.4mL). The resulting mixture was cooled using an ice/water bath. A 40% wtsolution of diethyl azodicarboxylate (2.8 mL, 6.19 mmol) was then addeddropwise and the resulting mixture allowed to warm to room temperaturewith stirring overnight. The resulting mixture was concentrated in vacuoand the resulting residue purified using the Analogix IF-280, 150 gcolumn, 95:5-90:10 Heptane:EtOAc to yield ethyl3-(4-((5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate.

¹H NMR (CHLOROFORM-d) δ: 6.93-7.05 (m, 3H), 6.65-6.72 (m, 2H), 5.08 (s,2H), 4.13 (q, J=7.8 Hz, J=11.7 Hz, 2H), 2.86-2.96 (m, 2H), 2.47-2.57 (m,2H), 2.24 (s, 6H), and 1.25 (t, J=7.8 Hz, 3H).

d)3-(4-((5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

A 50 mL round bottom flask was charged with ethyl3-(4-((5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(215.6 mg, 0.492 mmol), tetrahydrofuran (4.1 mL), water (1.7 mL), andlithium hydroxide (206 mg, 4.92 mmol). The resulting mixture was stirredat room temperature overnight. The resulting mixture was washed withdiethyl ether. The resulting residue was then acidified with 2N HCl. Theresulting mixture was extracted with ethyl acetate (2×100 mL). Theorganic layers were dried with magnesium sulfate, filtered andconcentrated in vacuo. The resulting residue was purified using theAnalogix IF-280, 40 g column, 90:10-50:50 heptane:EtOAc to yield3-(4-((5-fluoro-2-(trifluoromethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid.

¹H NMR (CHLOROFORM-d) δ: 6.94-7.05 (m, 3H), 6.66-6.74 (m, 2H), 5.08 (s,2H), 2.90-2.98 (m, 2H), 2.55-2.65 (m, 2H), and 2.25 (s, 6H); LC/MS (ES+)m/z 434 (M+Na).

Example 853-(4-((3,5-difluoro-2-methylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

a) Methyl 5-fluoro-2-methylbenzofuran-7-carboxylate

A 20 mL sealed tube was charged with methyl3-bromo-5-fluoro-2-hydroxybenzoate (1.39 g, 4.01 mmol) and 4.0 mL ofdimethylformamide. The resulting mixture was cooled using a dry ice andacetone bath to −78° C. Inot the resulting mixture was then bubbledpropyne for 10 minutes, followed by addition of copper iodide (76.5 mg,0.402 mmol) and PdCl₂(Ph₃P)₂ (281 mg, 0.402 mmol). The resulting mixturewas flushed with argon, the tube sealed and the resulting mixturestirred at room temperature for 1 h, then heated to 75° C. and stirredovernight. The resulting mixture was concentrated in vacuo and theresulting residue purified using the Analogix IF-280, 150 g column, 95:5Heptane:EtOAc to yield methyl 5-fluoro-2-methylbenzofuran-7-carboxylate,which was used directly in the next step.

¹H NMR (CHLOROFORM-d) δ: 7.50-7.59 (m, 1H), 7.28-7.36 (m, 1H), 6.40 (s,1H), 3.98 (s, 3H), and 2.52 (s, 3H).

b) Methyl2-bromo-3,5-difluoro-2-methyl-2,3-dihydrobenzofuran-7-carboxylate

A polypropylene tube was charged with N-bromosuccinimide (222.3 mg, 1.25mmol) and diethyl ether (6.0 mL) and 70% pyridinium poly(hydrogenfluoride) solution (1.20 mL, 0.961 mmol). The tube was flushed withargon and cooled using a dry ice and acetone bath to −78° C. A solutionof methyl 5-fluoro-2-methylbenzofuran-7-carboxylate (200 mg, 0.961 mmol)in diethyl ether (1.0 mL) was added slowly. The resulting residue wasstirred and allowed to warm to room temperature overnight. The resultingmixture was poured into ice water and extract with diethyl ether. Theresulting mixture was washed with saturated sodium bicarbonate and theorganic layers dried with magnesium sulfate, filtered through CELITE andconcentrated in vacuo to yield methyl2-bromo-3,5-difluoro-2-methyl-2,3-dihydrobenzofuran-7-carboxylate, whichwas used without further purification.

¹H NMR (CHLOROFORM-d) δ: 7.58-7.65 (m, 1H), 7.28-7.35 (m, 1H), 5.29 (d,J=15.2 Hz, 1H), 3.94 (s, 3H) and 2.12 (d, J=18.2 Hz, 3H).

c) Methyl 3,5-difluoro-2-methylbenzofuran-7-carboxylate

A 50 mL round bottom flask was charged with methyl2-bromo-3,5-difluoro-2-methyl-2,3-dihydrobenzofuran-7-carboxylate (300mg, 0.977 mmol) and 9.8 mL of dimethylsulfoxide. To the resultingmixture was then added 1,8-diazobicycloundec-7-ene (0.29 mL, 1.95 mmol)and the mixture stirred at room temperature overnight. The resultingmixture was diluted with diethyl ether and washed with saturated aqueousammonium chloride. The organic layers were dried with magnesium sulfate,filtered through CELITE and concentrated in vacuo to yield methyl3,5-difluoro-2-methylbenzofuran-7-carboxylate, which was used withoutfurther purification.

¹H NMR (CHLOROFORM-d) δ: 7.59-7.67 (m, 1H), 7.26-7.34 (m, 1H), 4.00 (s,3H), and 2.55 (s, 3H).

d) (3,5-difluoro-2-methylbenzofuran-7-yl)methanol

A 50 mL round bottom flask was charged with methyl3,5-difluoro-2-methylbenzofuran-7-carboxylate (280 mg, 1.24 mmol) and3.3 mL of dichloromethane. The resulting mixture was cooled using a dryice and acetone bath to −78° C. To the resulting mixture was then addeddropwise via syringe a dichloromethane solution of DIBAL (5.0 mL, 5.0mmol). The resulting mixture was warmed to room temperature over 20minutes, then poured into aqueous sodium hydroxide solution (50 mL). Thelayers were separated and the aqueous layer extracted three more timeswith ethyl acetate (100 mL each time). The organic layers were driedwith magnesium sulfate, filtered through CELITE and concentrated invacuo to yield (3,5-difluoro-2-methylbenzofuran-7-yl)methanol, which wasused without further purification.

e) Ethyl3-(4-((3,5-difluoro-2-methylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

A 50 mL round bottom flask was charged with ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate (0.875 g, 3.94 mmol),(3,5-difluoro-2-methylbenzofuran-7-yl)methanol (390 mg mg, 1.97 mmol),triphenylphosphine (0.805 g, 3.07 mmol) and tetrahydrofuran (2.8 mL).The resulting mixture was cooled using an ice/water bath. To theresulting mixture was then added a 40% wt solution of diethylazodicarboxylate (1.4 mL, 3.17 mmol) dropwise and the mixture allowed towarm to room temperature with stirring overnight. The resulting mixturewas concentrated in vacuo and the resulting residue purified using theAnalogix IF-280, 40 g column, 95:5-90:10 Heptane:EtOAc to yield ethyl3-(4-((3,5-difluoro-2-methylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate.

¹H NMR (CHLOROFORM-d) δ: 7.12-7.18 (m, 1H), 6.99-7.05 (m, 1H), 6.71-6.77(m, 1H), 6.61-6.67 (m, 1H), 5.25 (s, 2H), 4.13 (q, J=7.8 Hz, J=11.7 Hz,2H), 2.85-2.96 (m, 2H), 2.47-2.56 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H),2.20 (s, 3H), and 1.25 (t, J=7.8 Hz, 3H).

f)3-(4-((3,5-difluoro-2-methylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid

A 100 mL round bottom flask was charged with ethyl3-(4-((3,5-difluoro-2-methylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(209.6 mg, 0.521 mmol), tetrahydrofuran (4.3 mL), water (1.8 mL), andlithium hydroxide (219 mg, 5.21 mmol). The resulting mixture was stirredat room temperature rt overnight. The resulting mixture was washed withdiethyl ether. The resulting residue was then acidified with 2N HCl. Theresulting mixture was extracted with ethyl acetate (2×100 mL). Theorganic layers were dried with magnesium sulfate, filtered andconcentrated in vacuo. The resulting residue was purified using theAnalogix IF-280, 40 g column, 90:10-50:50 Heptane:EtOAc to yield3-(4-((3,5-difluoro-2-methylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid.

¹H NMR (CHLOROFORM-d) δ: 7.14-7.20 (m, 1H), 7.03-7.07 (m, 1H), 6.73-6.80(m, 1H), 6.64-6.70 (m, 1H), 5.29 (s, 2H), 2.89-2.97 (m, 2H), 2.55-2.64(m, 2H), 2.45 (s, 3H), and 2.25 (s, 6H); LC/MS (ES+) m/z 375 (M+1).

Example 863-{4-[(2,3-Dimethyl-1-benzofuran-4-yl)methoxy]-2,3-difluorophenyl}propanoicacid

a) (E)-Ethyl 3-(2,3-difluoro-4-hydroxyphenyl)acrylate

A mixture of 4-bromo-2,3-difluorophenol (14.37 g, 66 mmol), TEA (33 mL,237.4 mmol), ethyl acrylate (22.33 mL, 204.35 mmol), Pd(OAc)₂ (0.77 g,3.45 mmol) and tri-o-tolylphosphine (1.40 g, 4.61 mmol) in DMF (30 mL)in a pressure tube was degassed/refilled with argon and then heated at110° C. overnight. The resulting residue was cooled to room temperature,EtOAc was added and the mixture stirred for 30 min. The resultingresidue was filtered through a pad of CELITE and the filtrate wasevaporated under vacuum. The resulting residue was acidified with 2N HClto pH ˜2 and extracted with EtOAc. The combined organic fractions werewashed with water, brine and dried over Na₂SO₄. The solvent wasevaporated under vacuum and the residue was purified by silica columnchromatography (40-50% EtOAc/heptane) to yield (E)-ethyl3-(2,3-difluoro-4-hydroxyphenyl)acrylate as a yellow solid.

¹H NMR (400 MHz, CHLOROFORM-d) └ ppm 1.34 (t, J=7.1 Hz, 3H), 4.27 (q,J=7.1 Hz, 2H), 6.45 (d, J=16.2 Hz, 1H), 6.76-6.87 (m, 1H), 7.15-7.24 (m,1H), 7.70 (d, J=16.2 Hz, 1H).

b) Ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate

To a solution of (E)-ethyl 3-(2,3-difluoro-4-hydroxyphenyl)acrylate(5.10 g, 20.58 mmol) in ethanol (100 mL) in a Parr bottle was added Pd/C(10%, 1.5 g). The vessel was charged with hydrogen (40 PSI) and shakenovernight. The catalyst was removed by filtration and the filtrateconcentrated in vacuo to yield ethyl3-(2,3-difluoro-4-hydroxyphenyl)propanoate.

c) (2,3-Dimethylbenzofuran-4-yl)methanol

A solution of methyl 2,3-dimethylbenzofuran-4-carboxylate (2 g, 9.79mmol, prepared as described in PCT Publication WO 2008/038251) in DCMwas cooled to −78° C. To the resulting solution was then added DIBAL(1M, 39.2 mL, 39.2 mmol) dropwise. The resulting solution was stirredfor 2h at −78° C. and allowed to warm to room temperature. The resultingsolution was cooled in an ice bath and quenched with saturated NH₄Cl andstirred for 1 h. The organic layer was decanted and the aqueous layerwas extracted three times with DCM. The combined organic layers werewashed with NaOH solution (1.0 M) and brine, then dried over Na₂SO₄ andconcentrated in vacuo to yield an oil. The oil was purified by columnchromatography to yield (2,3-dimethylbenzofuran-4-yl)methanol.

d) Ethyl3-(4-((2,3-dimethylbenzofuran-4-yl)methoxy)-2,3-difluorophenyl)propanoate

A solution of (2,3-dimethylbenzofuran-4-yl)methanol (76.5 mg, 0.43mmol), ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate (100 mg, 0.43mmol) and PPh₃ (114 mg, 0.43 mmol) in THF was cooled in an ice bath andtreated with diethylazodicarboxylate (68 uL, 0.43 mmol). The resultingsolution was stirred and allowed to warm to room temperature over 18 h.The solvent was removed under vacuum and the residue was purified bysilica preparative TLC to yield ethyl3-(4-((2,3-dimethylbenzofuran-4-yl)methoxy)-2,3-difluorophenyl)propanoate.

e)3-(4-((2,3-dimethylbenzofuran-4-yl)methoxy)-2,3-difluorophenyl)propanoicacid

A solution of ethyl3-(4-((2,3-dimethylbenzofuran-4-yl)methoxy)-2,3-difluorophenyl)propanoate(120 mg, 0.31 mmol) in MeOH was treated with NaOH (5M, 0.62 mL, 3.1mmol) and the resulting solution was stirred for 18 h. Methanol wasremoved under vacuum and the residue was neutralized with 2N HCl andthen extracted with EtOAc. The solvent was removed under vacuum to yield3-(4-((2,3-dimethylbenzofuran-4-yl)methoxy)-2,3-difluorophenyl)propanoicacid.

¹H NMR (CHLOROFORM-d) δ: 7.35 (d, J=7.8 Hz, 1H), 7.03-7.14 (m, 2H),6.76-6.82 (m, 2H), 5.46 (s, 2H), 2.57-2.65 (m, 2H), 2.38 (s, 3H), 2.37(s, 3H), 2.30 (t, 2H).

Example 873-{2,3-Difluoro-4-[(2-methyl-1-benzofuran-4-yl)methoxy]phenyl}propanoicacid

a) Methyl 3-(prop-2-yn-1-yloxy)benzoate

To a solution of methyl 3-hydroxybenzoate (7.0 g, 46 mmol) in DMF wasadded K₂CO₃ (9.9 g, 71.8 mmol) and propargyl bromide (8.2 g, 66.7 mmol).The resulting suspension was stirred for 18 h, diluted with water andextracted with EtOAc (×2). The organic layers were combined, dried oversodium sulfate, filtered and concentrated in vacuo. The resultingresidue was purified by chromatography (0-20% EtOAc/heptane) to yieldmethyl 3-(prop-2-yn-1-yloxy)benzoate.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.55 (t, J=2.4 Hz, 1H), 3.91 (s,3H), 4.73 (d, J=2.4 Hz, 2H), 7.17 (dt, J=6.7, 1.5 Hz, 1H), 7.36 (t,J=7.9 Hz, 1H), 7.63 (dd, J=2.7, 1.5 Hz, 1H), 7.65-7.71 (m, 1H).

b) Methyl 2-methylbenzofuran-4-carboxylate

A solution of methyl 3-(prop-2-yn-1-yloxy)benzoate (2.2 g, 11.7 mmol),and CsF (2.3 g, 15.4 mmol) in N,N-diethylaniline (20 mL) was refluxedfor 5 h. The reaction mixture was cooled to room temp and diluted withEtOAc. The EtOAc solution was extracted with 2N HCl (×3). The organicfraction was washed with brine, dried over Na₂SO₄ and evaporated. Theresulting residue was purified by silica gel column chromatography toyield methyl 2-methylbenzofuran-4-carboxylate.

c) (2-Methylbenzofuran-4-yl)methanol

A solution of methyl 2-methylbenzofuran-4-carboxylate (0.73 g, 3.84mmol, prepared as described in ISHIKAWA, T., et al., Heterocycles, 1994,pp 371-80, Vol. 39(1)) in DCM was cooled to −78° C. To the resultingmixture was then added DIBAL (1M, 15.4 mL, 15.4 mmol) dropwise. Theresulting solution was stirred for 20 min at −78° C. and allowed to warmto room temperature. The resulting solution was poured into a mixture of1N NaOH and ice and extracted with EtOAc. The combined organic fractionswere washed with NaOH solution (1.0M) and brine, dried over Na₂SO₄ andconcentrated in vacuo to yield an oil which was purified by columnchromatography to yield (2-methylbenzofuran-4-yl)methanol.

d) Ethyl3-(2,3-difluoro-4-((2-methylbenzofuran-4-yl)methoxy)phenyl)propanoate

A solution of (2-methylbenzofuran-4-yl)methanol (70.5 mg, 0.43 mmol),ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate (100 mg, 0.43 mmol,prepared as described in Example 86) and PPh₃ (114 mg, 0.43 mmol) in THFwas cooled in an ice bath and treated with diethylazodicarboxylate (68uL, 0.43 mmol). The resulting solution was stirred and allowed to warmto room temperature over 18 h. The solvent was removed under vacuum andthe residue was purified by silica preparative TLC to yield ethyl3-(2,3-difluoro-4-((2-methylbenzofuran-4-yl)methoxy)phenyl)propanoate.

e) 3-(2,3-Difluoro-4-((2-methylbenzofuran-4-yl)methoxy)phenyl)propanoicacid

A solution of ethyl3-(2,3-difluoro-4-((2-methylbenzofuran-4-yl)methoxy)phenyl)propanoate(116 mg, 0.31 mmol) in MeOH was treated with NaOH (5M, 0.62 mL, 3.1mmol) and the resulting solution was stirred for 18 h. Methanol wasremoved under vacuum and the residue was neutralized with 2N HCl andextracted with EtOAc. The solvent was removed under vacuum to yield3-(2,3-difluoro-4-((2-methylbenzofuran-4-yl)methoxy)phenyl)propanoicacid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.39-2.49 (m, 5H), 2.76 (t, J=7.7Hz, 2H), 5.33 (s, 2H), 6.56 (s, 1H), 6.74-6.90 (m, 2H), 7.13-7.22 (m,2H), 7.36-7.42 (m, 1H). ESI-MS (m/z): Calculated for C₁₉H₁₆F₂O₄: 369.1(M+Na); found: 369.1.

Example 883-{4-[(5-Chloro-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 5-chloro-2-ethyl benzofuran-7-carbaldehyde

A 20-mL sealed tube was charged with5-chloro-2-hydroxy-3-iodobenzaldehyde (5g, 12.7 mmol, 72%),dichlorobis(triphenylphosphine)palladium (0.89 g, 1.27 mmol),copper(I)iodide (0.24 g, 1.27 mmol), TEA (3.5 mL, 25.5 mmol) and 12.7 mLof DMF. The tube was flushed with argon, but-1-yne (1.4 g, 25.5 mmol)was introduced, and the resulting mixture stirred for 1 h at roomtemperature and at 75° C. overnight. The resulting residue was cooled toroom temperature, concentrated in vacuo and purified using the silicacolumn chromatography to yield5-chloro-2-ethylbenzofuran-7-carbaldehyde.

b) (5-Chloro-2-ethyl benzofuran-7-yl)methanol

To a solution of 5-chloro-2-ethylbenzofuran-7-carbaldehyde (390 mg, 1.87mmol) in MeOH cooled in an ice bath was added sodium borohydride (85 mg,2.24 mmol). The resulting mixture was stirred at room temperature for 2h. The resulting residue was extracted with EtOAc, dried over Na₂SO₄ andpurified by silica gel column chromatography to yield b)(5-Chloro-2-ethylbenzofuran-7-yl)methanol.

c)3-{4-[(5-Chloro-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting(5-chloro-2-ethylbenzofuran-7-yl)methanol according to the procedure asdescribed in Example 2.

¹H NMR (MeOD) δ: 7.41 (d, J=2.0 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 6.99(d, J=8.6 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.39 (s, 1H), 5.29 (s, 2H),2.89-2.98 (m, 2H), 2.82 (q, J=7.6 Hz, 2H), 2.50-2.57 (m, 2H), 2.25 (s,3H), 2.25 (s, 3H), 1.35 (t, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₂H₂₃ClO₄, 409.1 (M+Na), found 409.0.

Example 893-(4-{[5-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) 2-Methoxy-5-(trifluoromethoxy)benzaldehyde

To a solution of 1-methoxy-4-(trifluoromethoxy)benzene (25 g, 130.1mmol) in 500 mL of DCM at −78° C. was added titanium(IV)tetrachlorideover a period of 1 minute. The resulting mixture was stirred for 30minutes and dichloromethylmethyl ether (27.5 mL, 294.9 mmol) was added.The ice bath was allowed to expire and the mixture was stirred at roomtemperature overnight. The resulting residue was poured carefully intowater and extracted with three portions of DCM. The combined extractswere washed with water and brine, dried (Na₂SO₄), and concentrated. Theresulting residue was purified by flash column chromatography to yield2-methoxy-5-(trifluoromethoxy)benzaldehyde.

b) 2-Hydroxy-5-(trifluoromethoxy)benzaldehyde

To a solution of 2-methoxy-5-(trifluoromethoxy)benzaldehyde (19.5 g,88.6 mmol) in DCM at −78° C. was added boron tribromide (17.6 mL, 186.0mmol) over a period of ca.1 min. The resulting mixture was stirred for 1hour, the cooling bath was replaced with an ice bath and the mixture wasstirred for 1 hour. The resulting residue was slowly poured on to iceand extracted with DCM (×2). The extracts were dried (Na₂SO₄) andconcentrated. The resulting residue was purified by silica columnchromatography to yield 2-hydroxy-5-(trifluoromethoxy)benzaldehyde.

c) 2-Hydroxy-3-iodo-5-(trifluoromethoxy)benzaldehyde

A solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (20 g, 97.0mmol) and NIS (54.6 g, 242.7 mmol) in DMF (196 mL) was stirred at roomtemperature under Argon for 48 hr. The DMF was removed under vacuum andthe residue taken up in EtOAc and washed with 1N HCl, sodium thiosulfateand sat NaCl. The organic layer was dried over Na₂SO₄ and evaporated.The resulting residue was purified by silica gel chromatography (0 to30% EtOAc/hept over 20 min) to yield2-hydroxy-3-iodo-5-(trifluoromethoxy)benzaldehyde.

d) 2-Propyl-5-(trifluoromethoxy)benzofuran-7-carbaldehyde

The title compound was prepared by reacting2-hydroxy-3-iodo-5-(trifluoromethoxy)benzaldehyde according to theprocedure as described in Example 88 step (a) substituting pent-1-ynefor but-1-yne.

e) (2-Propyl-5-(trifluoromethoxy)benzofuran-7-yl)methanol

The title compound was prepared by reacting2-propyl-5-(trifluoromethoxy)benzofuran-7-carbaldehyde by reduction withNaBH₄ according to the procedure as described in Example 88 step (b).

f)3-(4-{[2-Ethyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting(2-propyl-5-(trifluoromethoxy)benzofuran-7-yl)methanol according to theprocedure described in Example 2.

¹H NMR (CHLOROFORM-d) δ: 7.29 (s, 1H), 7.26 (s, 1H), 6.99 (d, J=8.6 Hz,1H), 6.82 (d, J=8.6 Hz, 1H), 6.42 (s, 1H), 5.31 (s, 2H), 2.91-2.99 (m,2H), 2.81 (q, J=7.6 Hz, 2H), 2.56-2.64 (m, 2H), 2.25 (s, 6H), 1.34 (t,3H). Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₃F₃O₅, 437.1 (M+H),found 437.0.

Example 903-{4-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-difluorophenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 83 substituting ethyl3-(2,3-difluoro-4-hydroxyphenyl)propanoate (prepared as described inExample 86) for ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate.

¹H NMR (CHLOROFORM-d) δ: 7.12 (dd, J=8.3, 2.8 Hz, 1H), 7.05 (dd, J=9.6,2.5 Hz, 1H), 6.77-6.90 (m, 2H), 6.36 (s, 1H), 5.43 (s, 2H), 2.80-2.87(m, 2H), 2.77 (q, 2H), 2.47-2.56 (m, 2H), 1.30 (t, J=7.6 Hz, 3H). Massspectrum (ESI, m/z): Calculated for C₂₀H₁₇F₃O₄, 401.1 (M+Na), found401.0.

Example 913-{4-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]-3,5-difluorophenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 83 substituting ethyl3-(3,5-difluoro-4-hydroxyphenyl)propanoate (prepared as described inU.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011) for ethyl3-(4-hydroxy-2,3-dimethylphenyl)propanoate.

¹H NMR (CHLOROFORM-d) δ: 7.10 (d, J=9.1 Hz, 2H), 6.69-6.80 (m, 2H), 6.34(s, 1H), 5.40 (s, 2H), 2.83-2.92 (m, 2H), 2.77 (q, J=7.6 Hz, 2H),2.60-2.70 (m, 2H), 1.31 (t, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₀H₁₇F₃O₄, 401.1 (M+Na), found 401.0.

Example 923-{6-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2-(trifluoromethyl)pyridin-3-yl}propanoicacid

a) 6-Chloro-3-iodo-2-(trifluoromethyl)pyridine

A solution of LDA (1.8 M, 24.5 mL) in THF was cooled to −78 ° C. and asolution of 2-chloro-6-(trifluoromethyl)pyridine (4 g, 22.0 mmol) in THFwas added dropwise. The solution was stirred at −78° C. for 1.5 h. Tothe resulting mixture was then added a solution of iodine (5.6 g, 22.0mmol) in THF dropwise over 30 min. The solution was stirred at −78° C.for 45 min, then quenched with 2M HCl. The resulting mixture wasextracted with Et₂O (2×). The combined organic extracts were washed withsodium thiosulfate, sat NaHCO₃, brine and dried over Na₂SO₄ to yield6-chloro-3-iodo-2-(trifluoromethyl)pyridine.

b) (E)-Ethyl 3-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)acrylate

The title compound was prepared according to the procedure as describedin Example 86 step (a) substituting6-chloro-3-iodo-2-(trifluoromethyl)pyridine for4-bromo-2,3-difluorophenol.

c) (E)-Ethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-(trifluoromethyl)pyridin-3-yl)acrylate

To a solution of (2-ethyl-5-fluorobenzofuran-7-yl)methanol (362 mg, 1.86mmol, prepared as described in Example 83) in DMF was added NaH (60%, 80mg, 2.02 mmol) and the mixture stirred at room temperature for 1 hr. Tothe resulting solution was then added (E)-ethyl3-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)acrylate (434 mg, 1.55 mmol)dropwise and the resulting mixture stirred at room temperature for 72 h.DMF was removed under vacuum and the residue taken up in sat NH₄Cl andextracted into EtOAc. The organic fraction was concentrated and theresulting residue purified by silica gel column chromatography to yield(E)-ethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-(trifluoromethyl)pyridin-3-yl)acrylate.

d) Ethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-(trifluoromethyl)pyridin-3-yl)propanoate

To a solution of (E)-ethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-(trifluoromethyl)pyridin-3-yl)acrylate(230 mg, 0.53 mmol) in EtOAc was added bis(norbomadiene)rhodium(I)tetrafluoroborate (24 mg, 0.06 mmol) and the resulting mixture stirredunder a H₂ (balloon) atmosphere for 3h. The resulting residue wasconcentrated and purified by silica gel column chromatography to yieldethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-(trifluoromethyl)pyridin-3-yl)propanoate.

d)3-{6-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2-(trifluoromethyl)pyridin-3-yl}propanoicacid

The title compound was prepared by reacting ethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-2-(trifluoromethyl)pyridin-3-yl)propanoateaccording to the procedure described Example 1.

¹H NMR (MeOH) δ: 7.74 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.1 Hz, 1H), 7.16(dd, J=8.6, 2.5 Hz, 1H), 7.11 (dd, J=9.9, 2.8 Hz, 1H), 6.48 (t, J=1.0Hz, 1H), 5.69 (s, 2H), 2.95 (t, J=7.6 Hz, 2H), 2.82 (q, J=7.6 Hz, 2H),2.58-2.68 (m, 2H), 1.32 (t, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₀H₁₇F₄NO₄, 412.1 (M+H), found 412.0.

Example 933-{4-[(6-Ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 2-ethyl-5((2-methylallyl)oxy)benzofuran-7-carboxylate

To a solution of methyl 2-ethyl-5-hydroxybenzofuran-7-carboxylate (0.61g, 2.77 mmol, prepared as described in Example 33) in DMF (15 mL) wasadded potassium carbonate (0.84 g, 6.10 mmol) and3-chloro-2-methylprop-1-ene (0.63 mL, 6.10 mmol). The resultingsuspension was heated at 70° C. for 18 h, and then cooled to roomtemperature and solids filtered and washed with EtOAc. The EtOAcsolution was washed with water, brine, and dried over sodium sulfate,filtered and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography to yield methyl2-ethyl-5-((2-methylallyl)oxy)benzofuran-7-carboxylate.

b) Methyl 2-ethyl-5-hydroxy-6(2-methylallyl)benzofuran-7-carboxylate

Neat methyl 2-ethyl-5-((2-methylallyl)oxy)benzofuran-7-carboxylate (0.72g, 2.63 mmol) was heated at 192° C. for 18 hr. The resulting mixture wascooled and the resulting residue purified by silica columnchromatography to yield methyl2-ethyl-5-hydroxy-6-(2-methylallyl)benzofuran-7-carboxylate.

c) Methyl6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b═]difuran-4-carboxylate

A mixture of methyl2-ethyl-5-hydroxy-6-(2-methylallyl)benzofuran-7-carboxylate (0.20 g,0.73 mmol) in formic acid was heated at 100° C. for 18 hr. The formicacid was removed under vacuum and the residue dissolved in MeOH andtreated with TMS-diazomethane until a yellow color persisted. Theresulting residue was concentrated and purified by silica gel columnchromatography to yield methyl6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b]difuran-4-carboxylate.

d)(6-Ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran-4-yl)methanol

The title compound was prepared by reacting methyl6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran-4-carboxylatewith DIBAL according to the procedure as described in Example 86 step(c).

e)4-(Chloromethyl)-6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran

A mixture of(6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran-4-yl)methanol(40 mg, 0.16 mmol) and thionyl chloride (0.014 mL, 0.19 mmol) inmethylene chloride (2.8 mL) were stirred at room temperature under argonfor 4 hours. The resulting residue was concentrated and used in the nextstep without further purification.

f) Ethyl3-(4-((6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran-4-yl)methoxy)-2,3-dimethylphenyl)propanoate

A mixture of4-(chloromethyl)-6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran(43 mg, 0.16 mmol), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (72mg, 0.32 mmol) and cesium carbonate (137 mg, 0.42 mmol) in acetonitrile(2.9 mL) was heated at 70° C. under Ar overnight. The resulting residuewas filtered and the filtrate was concentrated and diluted with EtOAc,washed with brine, and dried over Na₂SO₄. The resulting residue waspurified by preparative TLC to yield ethyl3-(4-((6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran-4-yl)methoxy)-2,3-dimethylphenyl)propanoate.

g)3-{4-[(6-Ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting ethyl3-(4-((6-ethyl-2,2-dimethyl-2,3-dihydrobenzo[1,2-b:4,5-b′]difuran-4-yl)methoxy)-2,3-dimethylphenyl)propanoateaccording to the procedure as described in Example 1.

¹H NMR (CHLOROFORM-d) δ: 6.94-7.01 (m, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.75(s, 1H), 6.29 (s, 1H), 5.25 (s, 2H), 3.12 (s, 2H), 2.90-2.99 (m, 2H),2.75 (q, J=7.4 Hz, 2H), 2.55-2.65 (m, 2H), 2.23 (s, 3H), 2.17 (s, 3H),1.47 (s, 6H), 1.30 (t, J=7.6 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₆H₃₀O₅, 423.2 (M+H), found 423.0.

Example 943-{4-[(5-Chloro-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 5-chloro-2-hydroxy-3-iodobenzoate

A solution of methyl 5-chloro-2-hydroxybenzoate (2 g, 10.7 mmol) and NIS(6.0 g, 26.8 mmol) in DMF (22 mL) was stirred at room temperature underAr for 48 hr. DMF was removed under vacuum and the residue taken up inEtOAc and washed with 1N HCl, sodium thiosulfate and sat NaCl. Theorganic layer was dried over Na₂SO₄ and evaporated. The resultingresidue was purified by silica gel column chromatography (0 to 30% EtOAcin heptane over 20 min) to yield methyl5-chloro-2-hydroxy-3-iodobenzoate.

b) Methyl 5-chloro-2-propyl benzofuran-7-carboxylate

The title compound was prepared by reacting methyl5-chloro-2-hydroxy-3-iodobenzoate according to the procedure asdescribed in Example 83 substituting 1-pentyne for 1-butyne in step (b).

c) (5-Chloro-2-propylbenzofuran-7-yl)methanol

The title compound was prepared by reacting methyl5-chloro-2-propylbenzofuran-7-carboxylate according to the procedure asdescribed in Example 83 step (c).

d)3-{4-[(5-Chloro-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting(5-chloro-2-propylbenzofuran-7-yl)methanol according to the procedure asdescribed in Example 83.

¹H NMR (CHLOROFORM-d) δ: 7.40 (s, 1H), 7.33 (s, 1H), 6.98 (d, J=8.3 Hz,1H), 6.81 (d, J=8.3 Hz, 1H), 6.36 (s, 1H), 5.28 (s, 2H), 2.95 (t, J=7.8Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 2.57-2.66 (m, 2H), 2.25 (s, 6H),1.70-1.83 (m, 2H), 1.01 (t, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₃H₂₅ClO₄, 423.1 (M+Na), found 423.0.

Example 953-(4-{[2-(Difluoromethyl)-5-fluoro-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Methyl3-(4-((5-fluoro-2-(hydroxymethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

A solution of3-(4-((5-fluoro-2-(hydroxymethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoicacid (30 mg, 0.08 mmol, prepared as described in Example 5) in MeOH wascooled in an ice bath and treated with TMS-diazomethane until apermanent yellow color was obtained. Excess diazomethane was quenchedwith AcOH and solvent evaporated. The resulting residue was used in thenext step without further purification.

b) Methyl3-(4-((5-fluoro-2-formylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a solution of methyl3-(4-((5-fluoro-2-(hydroxymethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(31 mg, 0.08 mmol) in DCM (2 mL) was added Dess-Martin periodinane (40mg, 0.09 mmol) and the resulting mixture stirred for 4 hr at roomtemperature. The resulting residue was diluted with EtOAc and washedwith sat Na₂CO₃. The resulting residue was purified by prep-TLC to yieldmethyl3-(4-((5-fluoro-2-formylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate.

c) Methyl3-(4-((2-(difluoromethyl)-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a solution of methyl3-(4-((5-fluoro-2-formylbenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(30 mg, 0.08 mmol) in methanol was added bis(2-methoxyethyl)aminosulfurtrifluoride (0.04 mL, 0.23 mmol) and the mixture stirred for 18 hr. thesolution was concentrated and purified by preparative TLC to yieldmethyl3-(4-((2-(difluoromethyl)-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate.

d)3-(4-{[2-(Difluoromethyl)-5-fluoro-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting methyl3-(4-((2-(difluoromethyl)-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoateaccording to the procedure as described in Example 1.

¹H NMR (CHLOROFORM-d) δ: 7.32 (dd, J=9.6, 2.0 Hz, 1H), 7.23-7.25 (m,1H), 7.04 (s, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 6.75(t, J=54.4 Hz, 1H), 5.34 (s, 2H), 2.90-3.00 (m, 2H), 2.56-2.66 (m, 2H),2.26 (s, 3H), 2.24 (s, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₁H₁₉F₃O₄, 415.1 (M+Na), found 415.0.

Example 963-{6-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]-4-methylpyridin-3-yl}propanoicacid

a) Ethyl 3-(6-fluoro-4-methylpyridin-3-yl)propanoate

The title compound was prepared according to the procedure as describedin Example 86 substituting 5-bromo-2-fluoro-4-methylpyridine for4-bromo-2,3-difluorophenol in step (a).

b) Ethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-4-methylpyridin-3-yl)propanoate

To a solution of (2-ethyl-5-fluorobenzofuran-7-yl)methanol (314 mg, 1.62mmol, prepared as described in Example 83) in DMF was added NaH (60%, 70mg, 1.75 mmol) and the resulting mixture stirred at room temperature for1 hr. To the resulting solution (ethyl3-(6-fluoro-4-methylpyridin-3-yl)propanoate (284 mg, 1.35 mmol) in DMFwas added dropwise and the mixture stirred at room temperature for 72h.DMF was removed under vacuum and the residue was purified by silica gelcolumn chromatography to yield ethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-4-methylpyridin-3-yl)propanoate.

c)3-{6-[(2-Ethyl-5-fluoro-1-benzofuran-7-yl)methoxy]-4-methylpyridin-3-yl}propanoicacid

The title compound was prepared by reacting ethyl3-(6-((2-ethyl-5-fluorobenzofuran-7-yl)methoxy)-4-methylpyridin-3-yl)propanoateaccording to the procedure as described in Example 1.

¹H NMR (MeOD) δ: 7.96 (s, 1H), 7.12 (dd, J=8.6, 2.5 Hz, 1H), 7.05 (dd,J=9.6, 2.5 Hz, 1H), 6.84 (s, 1H), 6.42 (s, 1H), 5.59 (s, 2H), 2.93 (t,J=7.8 Hz, 2H), 2.81 (q, J=7.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.38 (s,3H), 1.28-1.43 (m, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₀H₂₀FNO₄, 358.1 (M+H), found 358.0.

Example 973-{6-[(5-Chloro-2-propyl-1-benzofuran-7-yl)methoxy]-4-methylpyridin-3-yl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 96 substituting (5-chloro-2-propylbenzofuran-7-yl)methanol(prepared as described in Example 94) for(2-ethyl-5-fluorobenzofuran-7-yl)methanol.

¹H NMR (CHLOROFORM-d) δ: 8.22 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.27 (s,1H), 6.90 (s, 1H), 6.36 (s, 1H), 5.60 (s, 2H), 2.94 (t, J=7.3 Hz, 2H),2.73 (t, J=7.3 Hz, 2H), 2.63-2.70 (m, 2H), 2.42 (s, 3H), 1.76 (sxt,J=7.5 Hz, 2H), 1.00 (t, J=7.3 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₁H₂₂ClNO₄, 388.1 (M+H), found 388.0.

Example 983-(2,3-Dimethyl-4-{[2-propyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 89 substituting pent-1-yne for but-1-yne.

¹H NMR (CHLOROFORM-d) δ: 7.24-7.31 (m, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.82(d, J=8.6 Hz, 1H), 6.42 (s, 1H), 5.31 (s, 2H), 2.91-3.00 (m, 2H), 2.76(t, J=7.6 Hz, 2H), 2.56-2.66 (m, 2H), 2.25 (s, 6H), 1.78 (sxt, J=7.4 Hz,2H), 1.02 (t, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₅F₃O₅,451.2 (M+H), found 451.0.

Example 993-(2,3-Dimethyl-4-{[2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 89 substituting prop-1-yne for but-1-yne.

¹H NMR (CHLOROFORM-d) δ: 7.22-7.30 (m, 2H), 6.99 (d, J=8.6 Hz, 1H), 6.80(d, J=8.1 Hz, 1H), 6.41 (d, J=1.0 Hz, 1H), 5.30 (s, 2H), 2.90-2.99 (m,2H), 2.56-2.66 (m, 2H), 2.47 (s, 3H), 2.25 (s, 6H). Mass spectrum (ESI,m/z): Calculated for C₂₂H₂₁F₃O₅, 423.1 (M+H), found 423.0.

Example 1003-{4-[(5-Chloro-2-propyl-1-benzofuran-7-yl)methoxy]-3-cyano-2-methylphenyl}propanoicacid

a) 3-Bromo-6-fluoro-2-methylbenzonitrile

To a cooled (0° C.) solution of 2-fluoro-6-methylbenzonitrile (2 g, 14.8mmol) in concentrated sulfuric acid (40 mL) was added NBS (2.7 g, 15.6mmol). The resulting residue was stirred at 0° C. for 3 hrs and pouredinto ice-water (400 mL). The resulting solution was extracted threetimes with EtOAc (80 mL) and the combined organic layers were washedwith water and brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography to yield 3-bromo-6-fluoro-2-methylbenzonitrile.

b) Ethyl 3-(3-cyano-4-fluoro-2-methylphenyl)propanoate

The title compound was prepared by reacting3-bromo-6-fluoro-2-methylbenzonitrile according to the procedure asdescribed in Example 86.

c)3-{4-[(5-Chloro-2-propyl-1-benzofuran-7-yl)methoxy]-3-cyano-2-methylphenyl}propanoicacid

The title compound was prepared by reacting ethyl3-(3-cyano-4-fluoro-2-methylphenyl)propanoate and(5-chloro-2-propylbenzofuran-7-yl)methanol (prepared as described inExample 94) according to the procedures as described in Example 96.

¹H NMR (CHLOROFORM-d) δ: 7.41 (d, J=2.0 Hz, 1H), 7.32 (d, J=1.8 Hz, 1H),7.23-7.25 (m, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.37 (s, 1H), 5.42 (s, 2H),2.92 (t, J=7.7 Hz, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.60 (t, J=7.7 Hz, 2H),2.51 (s, 3H), 1.78 (sxt, 2H), 1.02 (t, J=7.5 Hz, 3H). Mass spectrum(ESI, m/z): Calculated for C₂₃H₂₂ClNO₄, 431.1 (M+H), found 431.0.

Example 1013-{4-[(5-Bromo-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 5-bromo-2-ethylbenzofuran-7-carboxylate

The title compound was prepared according to the procedure as describedin Example 83 step (b) substituting methyl5-bromo-2-hydroxy-3-iodobenzoate for methyl3-bromo-5-fluoro-2-hydroxybenzoate

b)3-{4-[(5-Bromo-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl5-bromo-2-ethylbenzofuran-7-carboxylate according to the procedure asdescribed in Example 83.

¹H NMR (MeOD) δ: 7.57 (d, J=2.0 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 6.99(d, J=8.3 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 5.29 (s, 2H),2.89-2.99 (m, 2H), 2.82 (q, J=7.6 Hz, 2H), 2.49-2.59 (m, 2H), 2.26 (s,3H), 2.25 (s, 3H), 1.35 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₂H₂₃BrO₄, 431.1 (M+H), found 431.0.

Example 1023-{4-[(5-Fluoro-2,3-dimethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 3-(2-Bromo-4-fluorophenoxy)butan-2-one

A mixture of 2-bromo-4-fluorophenol (5 g, 26.2 mmol), potassiumcarbonate (10.8 g, 78.5 mmol), 3-chlorobutan-2-one (2.6 mL, 26.2 mmol),and potassium iodide (1.2 g, 7.4 mmol) in acetonitrile (20 mL) washeated to 70° C. and stirred for 18 h. The resulting residue was cooledto room temperature and the solids removed by filtration. The filtratewas concentrated under vacuum and the residue taken up in EtOAc andwashed with water and saturated NaCl. The solution was dried over Na₂SO₄and evaporated and the residue purified by silica gel chromatography toyield 3-(2-bromo-4-fluorophenoxy)butan-2-one.

b) 7-Bromo-5-fluoro-2,3-dimethylbenzofuran

3-(2-Bromo-4-fluorophenoxy)butan-2-one (4g, 15.3 mmol) was added inportions to sulfuric acid (2 mL) at 30° C. and stirred for 6 hr. Theresulting residue was cooled to room temperature and poured on to ice.The resulting ac. mixture was extracted with EtOAc. The EtOAc fractionwas washed with 1N NaOH, water and saturated NaCl. The EtOAc fractionwas dried over Na₂SO₄ and evaporated and the residue purified by silicagel chromatography to yield 7-bromo-5-fluoro-2,3-dimethylbenzofuran.

c) 5-Fluoro-2,3-dimethylbenzofuran-7-carbaldehyde

To a solution of 7-bromo-5-fluoro-2,3-dimethylbenzofuran (1.56 g, 6.42mmol) in THF (30 mL) at −78° C. was added n-BuLi (1.6M hex, 4.41 mL).After stirring at this temperature for 30 min DMF (2.5 mL, 32.09 mmol)was added and the mixture was stirred for 1 h and then warmed to roomtemperature. Aqueous NH₄Cl was added and the aqueous phase was extractedwith EtOAc. The EtOAc phase was dried over MgSO₄, filtered, andevaporated under reduced pressure. The resulting residue was purified bysilica gel chromatography to yield5-fluoro-2,3-dimethylbenzofuran-7-carbaldehyde.

d)3-{4-[(5-Fluoro-2,3-dimethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting5-fluoro-2,3-dimethylbenzofuran-7-carbaldehyde according to theprocedure as described in Example 88.

¹H NMR (CHLOROFORM-d) δ: 7.09 (dd, J=9.9, 2.3 Hz, 1H), 6.95-7.03 (m,2H), 6.79 (d, J=8.6 Hz, 1H), 5.29 (s, 2H), 2.95 (t, J=7.8 Hz, 2H),2.56-2.65 (m, 2H), 2.39 (s, 3H), 2.25 (s, 3H), 2.25 (s, 3H), 2.13 (s,3H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₃FO₄, 371.1 (M+H),found 471.0.

Example 1033-(7-{[2-Methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dihydro-1H-inden-4-yl)propanoicacid

a) (2-Methyl-5-(trifluoromethoxy)benzofuran-7-yl)methanol

The title compound was prepared according to the procedure as describedin Example 89 substituting propyne for but-1-yne.

b)3-(7-{[2-Methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dihydro-1H-inden-4-yl)propanoicacid

The title compound was prepared by reacting(2-methyl-5-(trifluoromethoxy)benzofuran-7-yl)methanol and ethyl3-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate (prepared as describedin U.S. Pat. Appl. Publ., 20110313003, 22 Dec. 2011), according to theprocedure as described in Example 87.

¹H NMR (CHLOROFORM-d) δ: 7.27 (s, 1H), 7.23 (s, 1H), 6.96 (d, J=8.6 Hz,1H), 6.75 (d, J=8.1 Hz, 1H), 6.41 (d, J=1.0 Hz, 1H), 5.34 (s, 2H), 2.96(t, J=7.3 Hz, 2H), 2.86-2.93 (m, 4H), 2.59-2.68 (m, 2H), 2.48 (s, 3H),2.11 (quin, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₁F₃O₅, 435.1 (M+H), found 435.0.

Example 1043-{4-[(5-Chloro-2-propyl-1-benzofuran-7-yl)methoxy]-2,3-difluorophenyl}propanoicacid

The title compound was prepared by reacting(5-chloro-2-propylbenzofuran-7-yl)methanol (prepared as described inExample 94 step b) and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate(prepared as described in Example 86 step b) according to the procedureas described in Example 87.

¹H NMR (CHLOROFORM-d) δ: 7.41 (d, J=2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H),6.81-6.89 (m, 1H), 6.71-6.80 (m, 1H), 6.36 (s, 1H), 5.36 (s, 2H),2.90-3.00 (m, 2H), 2.74 (t, J=7.6 Hz, 2H), 2.63-2.71 (m, 2H), 1.69-1.85(m, 2H), 1.01 (t, J=7.3 Hz, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₁H₁₉ClF₂O₄, 431.1 (M+Na), found 431.0.

Example 1053-{4-[(2,3-Dimethyl-1-benzofuran-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 86 substituting ethyl3-(2,3-dimethyl-4-hydroxyphenyl)propanoate for ethyl3-(2,3-difluoro-4-hydroxyphenyl)propanoate.

¹H NMR (CHLOROFORM-d) δ: 7.36 (d, J=7.1 Hz, 1H), 7.13-7.24 (m, 2H), 7.00(d, J=8.1 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 5.26 (s, 2H), 2.92-3.00 (m,2H), 2.57-2.67 (m, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H), 2.16(s, 3H).

Example 1063-(4-{[4,6-Difluoro-2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) 3,5-Difluoro-4-(trifluoromethoxy)phenol

To a solution of 5-bromo-1,3-difluoro-2-(trifluoromethoxy)benzene (20 g,72.2 mmol) in diethyl ether (200 mL) under an atmosphere of argon at−78° C. was slowly added a solution of n-BuLi (1.6M hexane, 49.6 mL).The resulting residue was stirred for 30 minutes and then added viacannula to a solution of trimethylborate (9.04 mL, 79.4 mmol) in diethylether (100 mL) at −70° C. After the addition was complete, thetemperature was allowed to rise to room temperature then recooled to−10° C. Glacial acetic acid (14.2 mL) was added followed by a solutionof 30% aqueous hydrogen peroxide (20 mL) in water (20 mL) whilemaintaining the solution at 0° C. The resulting solution was allowed towarm to room temperature while stirring for an additional 40 min.Saturated aqueous ammonium chloride solution was added (200 mL) followedby tetrahydrofuran (100 mL), and the organic layer was separated, washedwith sat NaHCO₃, water (300 mL), and brine (100 mL), dried withmagnesium sulfate, and filtered. The solvent was removed under vacuumand the residue was purified by silica gel column chromatography toyield 3,5-difluoro-4-(trifluoromethoxy)phenol.

b) 1,3-Difluoro-5-methoxy-2-(trifluoromethoxy)benzene

A mixture of 3,5-difluoro-4-(trifluoromethoxy)phenol (10 g, 46.71 mmol),potassium carbonate (19.37 g, 140.13 mmol), and methyl iodide (8.72 mL,140.13 mmol), in 28 mL of acetone was refluxed under Ar atmosphere for18 h. The solution was cooled to room temperature and filtered to removesolids. The filtrate was evaporated under vacuum and the residuepurified by silica gel column chromatography to yield1,3-difluoro-5-methoxy-2-(trifluoromethoxy)benzene.

c)3-(4-{[4,6-Difluoro-2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 89 substituting1,3-difluoro-5-methoxy-2-(trifluoromethoxy)benzene for1-methoxy-4-(trifluoromethoxy)benzene in step (a).

¹H NMR (CHLOROFORM-d) δ: 7.02 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H),6.51 (s, 1H), 5.27 (s, 2H), 2.85-3.01 (m, 2H), 2.55-2.68 (m, 2H), 2.46(s, 3H), 2.22 (s, 3H), 2.13 (s, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₂H₁₉F₅O₅, 481.1 (M+Na), found 481.0.

Example 1073-(2,3-Difluoro-4-{[6-fluoro-4-methoxy-2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid

To a solution of ethyl3-(4-((4,6-difluoro-2-methyl-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-difluorophenyl)propanoate(304 mg, 0.62 mmol, prepared as described in Example 108) in a mixtureof THF/MeOH was added NaOH (25 mg, 0.62 mmol) and the resulting mixturestirred at room temperature for 18 h. To the resulting mixture was thenadded 6N HCl until a precipitate formed, which was collected byfiltration and purified by silica gel chromatography to yield3-(2,3-difluoro-4-{[6-fluoro-4-methoxy-2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid.

¹H NMR (CHLOROFORM-d) δ: 6.78-6.97 (m, 2H), 6.56 (d, J=1.0 Hz, 1H), 5.34(s, 2H), 4.13 (s, 3H), 2.95 (t, J=7.6 Hz, 2H), 2.61-2.76 (m, 2H), 2.44(s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₁H₁₆F₆O₆, 501.1(M+Na), found 501.0.

Example 1083-(4-{[4,6-Difluoro-2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-difluorophenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 106 substituting ethyl3-(2,3-difluoro-4-hydroxyphenyl)propanoate (prepared as described inExample 86) for ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate.

¹H NMR (CHLOROFORM-d) δ: 6.79-6.95 (m, 2H), 6.51 (d, J=1.0 Hz, 1H), 5.36(s, 2H), 2.89-3.02 (m, 2H), 2.61-2.71 (m, 2H), 2.47 (s, 3H). Massspectrum (ESI, m/z): Calculated for C₂₀H₁₃F₇O₅, 489.0 (M+Na), found489.0.

Example 1093-{4-[(6-Chloro-2,3-dimethyl-1-benzofuran-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 3-chloro-5-hydroxybenzoate

3-Chloro-5-hydroxybenzoic acid (2 g, 11.6 mmol) was dissolved in MeOHand cooled in an ice bath. Hydrogen chloride gas was bubbled into thesolution for 10 min and the flask was capped and the solution wasallowed to warm to room temperature and stirred for 18 h. The resultingresidue was concentrated under vacuum and the residue was purified bysilica gel chromatography to yield methyl 3-chloro-5-hydroxybenzoate.

b) 3-Oxobutan-2-yl 3-chloro-5-((3-oxobutan-2-yl)oxy)benzoate

A mixture of methyl 3-chloro-5-hydroxybenzoate (2 g, 10.72 mmol),3-chloro-2-butanone (2.28 g, 21.44 mmol), potassium carbonate (4.44 g,32.15 mmol), and potassium iodide (0.48 g, 2.89 mmol) in acetone (20 mL)was stirred at reflux for 16 h. After cooling to room temperature waterand diethyl ether were added, the layers were separated and the ac.layer was extracted with diethyl ether. The combined organic layers werewashed with NaOH solution (1.0 M) and water, dried over Na₂SO₄ andconcentrated in vacuo to 3-oxobutan-2-yl3-chloro-5-((3-oxobutan-2-yl)oxy)benzoate.

c) 3-Oxobutan-2-yl 6-chloro-2,3-dimethylbenzofuran-4-carboxylate

3-oxobutan-2-yl 3-chloro-5-((3-oxobutan-2-yl)oxy)benzoate (0.24 g, 0.78mmol) was added in portions to sulfuric acid (0.1 mL) at 30° C. and thenstirred for 2 h. The resulting residue was cooled to room temperatureand poured on to ice. The resulting aqueous mixture was extracted withEtOAc. The EtOAc fraction was washed with 1N NaOH, water and saturatedNaCl. The EtOAc fraction was dried over Na₂SO₄ and evaporated and theresulting residue was purified by silica gel chromatography to yield3-oxobutan-2-yl 6-chloro-2,3-dimethylbenzofuran-4-carboxylate.

d) (6-Chloro-2,3-dimethylbenzofuran-4-yl)methanol

To a solution of 3-oxobutan-2-yl6-chloro-2,3-dimethylbenzofuran-4-carboxylate (0.15 g, 0.51 mmol) in DCM(1.3 mL) at −78° C. was added a 1M DCM solution of DIBAL (4.07 mlm 4.07mmol). After 45 min the solution was allowed to reach room temperatureand poured into sat NaCl and stirred for 2 hr. The resulting mixture wasfiltered through CELITE and washed with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated invacuo. The resulting residue was purified by silica gel chromatographyto (6-chloro-2,3-dimethylbenzofuran-4-yl)methanol.

e)3-{4-[(6-Chloro-2,3-dimethyl-1-benzofuran-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting(6-chloro-2,3-dimethylbenzofuran-4-yl)methanol according to theprocedure as described Example 83.

¹H NMR (CHLOROFORM-d) δ: 7.35 (d, J=2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H),7.00 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 5.21 (s, 2H), 2.92-2.99(m, 2H), 2.58-2.66 (m, 2H), 2.36 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H),2.17 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₃ClO₄, 409.1(M+Na), found 409.0.

Example 1103-{4-[(6-Chloro-2-methyl-1-benzofuran-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) (6-Chloro-2-methylbenzofuran-4-yl)methanol

The title compound was prepared according to the procedure as describedin Example 87 substituting methyl 3-chloro-5-hydroxybenzoate for methyl3-hydroxybenzoate.

b)3-{4-[(6-Chloro-2-methyl-1-benzofuran-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting(6-chloro-2-methylbenzofuran-4-yl)methanol according to procedure inExample 83.

¹H NMR (CHLOROFORM-d) δ: 7.38 (s, 1H), 7.26 (s, 2H), 6.97 (d, J=8.1 Hz,1H), 6.74 (d, J=8.6 Hz, 1H), 6.46 (s, 1H), 5.15 (s, 2H), 2.94 (t, J=8.1Hz, 2H), 2.53-2.67 (m, 2H), 2.45 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H)

Example 1113-{4-[(5-Chloro-2-methyl-1,3-benzoxazol-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) Methyl 5-chloro-2-hydroxy-3-nitrobenzoate

To a solution of methyl 5-chloro-2-hydroxybenzoate (5g, 26.8 mmol) insulfuric acid (40 mL) cooled in an ice bath was added dropwise a mixtureof nitric acid (4.6 mL) in sulfuric acid (5 mL). The resulting residuewas allowed to warm to room temp and stirred for 5 hr and poured on toice. The resulting solid that was formed was collected by filtration,washed with water and dried under high vacuum to yield methyl5-chloro-2-hydroxy-3-nitrobenzoate.

b) Methyl 3-amino-5-chloro-2-hydroxybenzoate

To a solution of methyl 5-chloro-2-hydroxy-3-nitrobenzoate (2g, 8.6mmol) in methanol (60 mL) and acetic acid (60 mL) was added iron powder(9.6 g, 171.5) and the mixture was heated at reflux for 1 h. Aftercooling to room temperature, the resulting mixture was filtered througha pad of CELITE, the solid was washed with EtOAc (3×) and the filtratewas evaporated. The black residue was taken up with EtOAc, washed withwater, saturated Na₂CO₃ and dried over Na₂SO₄. The EtOAc was evaporatedto yield methyl 3-amino-5-chloro-2-hydroxybenzoate.

c) Methyl 5-chloro-2-methylbenzo[d]oxazole-7-carboxylate

A solution of methyl 3-amino-5-chloro-2-hydroxybenzoate (1.32 g, 6.53mmol), triethylorthoacetate (4 mL, 21.2 mmol), and p-toluenesulfonicacid (40 mg, 0.21 mmol) was heated at 100° C. for 18 hours. Theresulting mixture was concentrated in vacuo and the resulting residuepurified by flash column chromatography on silica gel with 30%EtOAc/heptane to yield methyl5-chloro-2-methylbenzo[d]oxazole-7-carboxylate.

d)3-{4-[(5-Chloro-2-methyl-1,3-benzoxazol-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared by reacting methyl5-chloro-2-methylbenzo[d]oxazole-7-carboxylate according to theprocedure as described in Example 83.

¹H NMR (DMSO-d₆) δ: 12.14 (br. s., 1H), 7.77 (s, 1H), 7.49 (s, 1H),6.90-7.00 (m, 1H), 6.87 (d, J=8.6 Hz, 1H), 5.30 (s, 2H), 2.72-2.84 (m,3H), 2.64 (s, 3H), 2.40 (t, J=7.6 Hz, 3H), 2.15 (s, 4H), 2.13 (s, 3H).

Example 1123-(4-{[5-Chloro-2-(2,2-difluoroethyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Methyl 5-chloro-2-(2-hydroxyethyl)benzofuran-7-carboxylate

The title compound was prepared from methyl5-chloro-2-hydroxy-3-iodobenzoate (prepared as described in Example 94step (a)) and but-3-yn-1-ol (prepared as described in Example 1, step(a)).

b) Methyl 5-chloro-2-(2-oxoethyl)benzofuran-7-carboxylate

To a solution of methyl5-chloro-2-(2-hydroxyethyl)benzofuran-7-carboxylate (0.80 g, 3.14 mmol)in DCM (2 mL) was added Dess-Martin periodinane (1.60 g, 3.77 mmol) andthe mixture stirred for 4 hr at room temperature. The resulting residuewas purified by preparative TLC to yield methyl5-chloro-2-(2-oxoethyl)benzofuran-7-carboxylate.

c) Methyl 5-chloro-2-(2,2-difluoroethyl)benzofuran-7-carboxylate

To a solution of methyl 5-chloro-2-(2-oxoethyl)benzofuran-7-carboxylate(0.50 g, 1.98 mmol) in DCM (3 mL) was addedbis(2-methoxyethyl)aminosulfur trifluoride (1.10 mL, 5.94 mmol) and themixture was stirred for 18 hr. The resulting mixture was purified bysilica gel column chromatography (0-20% EtOAc/heptane) to yield methyl5-chloro-2-(2,2-difluoroethyl)benzofuran-7-carboxylate.

d) (5-Chloro-2-(2,2-difluoroethyl)benzofuran-7-yl)methanol

The title compound was prepared by DIBAL reduction of methyl5-chloro-2-(2,2-difluoroethyl)benzofuran-7-carboxylate according to theprocedure as described in Example 86 step (c).

e)3-(4-{[5-Chloro-2-(2,2-difluoroethyl)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting(5-chloro-2-(2,2-difluoroethyl)benzofuran-7-yl)methanol according to theprocedure as described in Example 83.

¹H NMR (MeOH) δ: 7.49 (d, J=2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 6.99(d, J=8.6 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.68 (s, 1H), 6.16 (tt,J=56.0, 4.4 Hz, 1H), 5.30 (s, 2H), 3.36-3.46 (m, 2H), 2.86-2.99 (m, 2H),2.49-2.59 (m, 2H), 2.26 (s, 3H), 2.24 (s, 3H).

Example 1133-(4-{[2-(2-Hydroxyethyl)-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) 2-(2-Hydroxyethyl)-5-(trifluoromethoxy)benzofuran-7-carbaldehyde

2-(2-Hydroxyethyl)-5-(trifluoromethoxy)benzofuran-7-carbaldehyde wasprepared from 2-hydroxy-3-iodo-5-(trifluoromethoxy)benzaldehyde(prepared as described in Example 89 step (c)) and but-3-yn-1-ol(prepared as described in Example 1 step a)).

b)2-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-5-(trifluoromethoxy)benzofuran-7-carbaldehyde

To an ice-cooled solution of2-(2-hydroxyethyl)-5-(trifluoromethoxy)benzofuran-7-carbaldehyde (1.45g, 5.29 mmol) in DCM (25 mL) was added dihydropyran (2.42 mL, 26.4 mmol)and p-toluenesulfonic acid monohydrate (9.1 mg, 0.053 mmol) and themixture was stirred at 0° C. for 10 min and at room temperature for 1.25h. The resulting residue was partitioned between diethyl ether and asolution made up of saturated brine (40 mL), saturated sodiumbicarbonate (40 mL), and water (80 mL). The organic phase was washedtwice with saturated brine, dried (MgSO₄—K₂CO₃), and evaporated in vacuoto yield2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-5-(trifluoromethoxy)benzofuran-7-carbaldehyde.

c)(2-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methanol

The title compound was prepared by NaBH₄ reduction of2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-5-(trifluoromethoxy)benzofuran-7-carbaldehydeaccording to the procedure as described in Example 88 step (b).

d) Ethyl3-(2,3-dimethyl-4-((2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)phenyl)propanoate

The title compound was prepared by reacting(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methanolaccording to Mitsonobu coupling according to procedure as described inExample 83 step(d).

e) Ethyl3-(4-((2-(2-hydroxyethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a solution of ethyl3-(2,3-dimethyl-4-((2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)phenyl)propanoate(1.6 g, 2.83 mmol) in ethanol (30 mL) was added pyridiniump-toluenesulfonate (0.30 g, 1.19 mmol) and the resulting solutionstirred at 55° C. for 2.5 hr. The ethanol was removed under vacuum andthe residue was poured in to a solution of 10% citric acid and extractedwith EtOAc. The EtOAc was removed under vacuum and the residue purifiedby silica gel column chromatography to yield ethyl3-(4-((2-(2-hydroxyethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate.

f)3-(4-{[2-(2-Hydroxyethyl)-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting ethyl3-(4-((2-(2-hydroxyethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoateaccording to the procedure as described in Example 1.

¹H NMR (MeOH) δ: 7.33 (s, 1H), 7.26 (s, 1H), 7.00 (d, J=8.6 Hz, 1H),6.83 (d, J=8.6 Hz, 1H), 6.59 (s, 1H), 5.33 (s, 2H), 3.95 (t, J=6.6 Hz,2H), 3.05 (t, J=6.8 Hz, 2H), 2.90-2.98 (m, 2H), 2.50-2.57 (m, 2H), 2.26(s, 3H), 2.24 (s, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₃F₃O₆, 453.1 (M+H), found 453.0.

Example 1143-{4-[(6-Chloro-2-methyl-1,3-benzoxazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

a) 2-Amino-3-bromo-5-chlorophenol

To a solution of 2-bromo-4-chloro-6-methoxyaniline (5 g, 21.14 mmol)dissolved in DCM at −78° C. was added boron tribromide (6.01 mL, 63.42mmol) dropwise. The resulting solution was allowed to warm to roomtemperature and stirred for 18 hr. The reaction was quenched by slowlyadding ice and the resulting mixture was evaporated under vacuum toremove DCM and diluted with water. The aqueous solution was neutralizedby adding NaOH and the solid that formed was collected by filtration,washed with water, and dried under vacuum to yield2-amino-3-bromo-5-chlorophenol

b) 4-Bromo-6-chloro-2-methylbenzo[d]oxazole

A solution of methyl 2-amino-3-bromo-5-chlorophenol (4.65 g, 20.90mmol), triethylorthoacetate (20 mL, 105.83 mmol), and p-toluenesulfonicacid (200 mg, 1.05 mmol) was heated at 100° C. for 18 hours. Thereaction was concentrated in vacuo and the resulting residue waspurified by flash column chromatography on silica gel with 30%EtOAc/heptane to yield 4-bromo-6-chloro-2-methylbenzo[d]oxazole.

c)3-{4-[(6-Chloro-2-methyl-1,3-benzoxazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 118 step (d) substituting4-bromo-6-chloro-2-methylbenzo[d]oxazole for4-bromo-2-methyl-6-(trifluoromethoxy)benzo[d]thiazole.

¹H NMR (MeOD) δ: 7.46-7.55 (m, 2H), 6.98 (d, J=8.3 Hz, 1H), 6.78 (d,J=8.3 Hz, 1H), 5.38 (s, 2H), 2.87-2.98 (m, 2H), 2.68 (s, 3H), 2.48-2.58(m, 2H), 2.27 (s, 3H), 2.26 (s, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₀H₂₀ClNO₄, 374 (M+H), found 374.

Example 1153-(4-{[2-(2,2-Difluoroethyl)-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared according to the procedure as describedin Example 95 substituting ethyl3-(4-((2-(2-hydroxyethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoateprepared as described in Example 113 step (e)) for3-(4-((5-fluoro-2-(hydroxymethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoatein step (b).

¹H NMR (CHLOROFORM-d) δ: 7.36 (s, 1H), 7.33 (s, 1H), 7.00 (d, J=8.6 Hz,1H), 6.80 (d, J=8.1 Hz, 1H), 6.68 (s, 1H), 6.12 (tt, J=55.9, 4.5 Hz,1H), 5.31 (s, 2H), 3.37 (td, J=15.9, 4.5 Hz, 2H), 2.89-3.00 (m, 2H),2.57-2.65 (m, 2H), 2.25 (s, 3H), 2.24 (s, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₁ F₅O₅, 495 (M+Na), found 495.

Example 1163-(4-{[2-(2-Fluoroethenyl)-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid (Mixture of E/Z)

a) Ethyl3-(4-((2-(2,2-difluoroethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

The title compound was prepared according to the procedure as describedin Example 95 substituting ethyl3-(4-((2-(2-hydroxyethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(prepared as described in Example 113) for3-(4-((5-fluoro-2-(hydroxymethyl)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoatein step (b).

b)3-(4-{[2-(2-Fluoroethenyl)-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid (Mixture of E/Z)

A solution of ethyl3-(4-((2-(2,2-difluoroethyl)-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate(50 mg, 0.10 mmol) in THF/MeOH was cooled in an ice bath and treatedwith NaOH (4 mg, 0.10 mmol) and stirred for 3h. To the resulting mixturewas then added HCl (6N) was added to bring the pH to ˜5 and theresulting precipitate collected and purified by reverse phase HPLC toyield3-(4-{[2-(2-Fluoroethenyl)-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid (mixture of E/Z). Mass spectrum (ESI, m/z): Calculated forC₂₀H₂₀F₄O₅, 475 (M+Na), found 475.

Example 1173-{4-[(6-Chloro-2-methyl-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid

The title compound was prepared according to the procedure as describedin Example 118 substituting 4-chloro-2,6-dibromoaniline for2,6-dibromo-4-(trifluoromethoxy)aniline in step (a).

¹H NMR (MeOD) δ: 7.81 (d, J=2.0 Hz, 1H), 7.62 (d, J=1.3 Hz, 1H), 6.98(d, J=8.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 5.54 (s, 2H), 2.90-2.96 (m,2H), 2.87 (s, 3H), 2.50-2.57 (m, 2H), 2.30 (s, 3H), 2.27 (s, 3H). Massspectrum (ESI, m/z): Calculated for C₂₀H₂₀ClNO₃S, 390 (M+H), found 390.

Example 1183-(2,3-Dimethyl-4-{[2-methyl-6-(trifluoromethoxy)-1,3-benzothiazol-4-yl]methoxy}phenyl)propanoicacid

a) N-(2,6-dibromo-4-(trifluoromethoxy)phenyl)acetamide

To a solution of 2,6-dibromo-4-(trifluoromethoxy)aniline (5.0 g, 14.9mmol) in acetic acid (10 mL) was added acetic anhydride (2.1 mL, 22.5mmol) and the mixture stirred for 48 hrs at 90° C. The resulting residuewas cooled to room temperature, poured into ice water and the resultingpercipitate collected by filtration, washed with water and dried undervacuum to yield N-(2,6-dibromo-4-(trifluoromethoxy)phenyl)acetamide.

b) N-(2,6-dibromo-4-(trifluoromethoxy)phenyl)ethanethioamide

To a solution of N-(2,6-dibromo-4-(trifluoromethoxy)phenyl)acetamide(5.5 g, 14.6 mmol) in toluene (90 mL) was added Lawesson's reagent (3.0g, 7.3 mmol) and the mixture heated to reflux for 2.5 hrs. The resultingresidue was concentrated and the resulting residue was purified bysilica gel chromatography to yieldN-(2,6-dibromo-4-(trifluoromethoxy)phenyl)ethanethioamide.

c) 4-Bromo-2-methyl-6-(trifluoromethoxy)benzo[d]thiazole

To a solution ofN-(2,6-dibromo-4-(trifluoromethoxy)phenyl)ethanethioamide (2.6 g, 6.7mmol) in DME (10 mL) was added copper(I)iodide (66 mg, 0.35 mmol),3,4,7,8-tetramethyl-1,10-phenanthroline (165 mg, 0.70 mmol), and cesiumcarbonate (3.3 g, 10.1 mmol) and the mixture was stirred at 81° C. for20 hrs. The resulting residue was filtered through CELITE andconcentrated, and the residue was purified by silica gel chromatographyto yield 4-bromo-2-methyl-6-(trifluoromethoxy)benzo[d]thiazole.

d) 2-Methyl-6-(trifluoromethoxy)benzo[d]thiazole-4-carboxylic acid

To a suspension of 4-bromo-2-methyl-6-(trifluoromethoxy)benzo[d]thiazole(1.85 g, 5.93 mmol), potassium carbonate (3.85 g, 27.83 mmol), Pd(OAc)₂(133 mg, 0.59 mmol), and 1,10-bis(diphenylphosphino)ferrocene (0.70 g,1.24 mmol) in DMF (13 mL) was bubbled in gaseous CO for 15 min. Theresulting residue was heated to 80° C. for 18 h with a balloon of CO.The resulting mixture was cooled and partitioned between saturatedaqueous NaHCO₃ and EtOAc, and filtered. The aqueous layer was separated,acidified with 10% citric acid and extracted with EtOAc. The EtOAc layerwas dried over Na₂SO₄ and evaporated to yield2-methyl-6-(trifluoromethoxy)benzo[d]thiazole-4-carboxylic acid, whichwas used in the next step without further purification.

e) Methyl 2-methyl-6-(trifluoromethoxy)benzo[d]thiazole-4-carboxylate

Thionyl chloride (1.31 mL, 18.10 mmol) was added dropwise to methano (5mL) at −5° C. and the mixture stirred at 0° C. for 15 minutes.2-Methyl-6-(trifluoromethoxy)benzo[d]thiazole-4-carboxylic acid (1.40 g,5.05 mmol) was introduced at the same temperature and the mixture wasstirred for 15 minutes, then kept at 70° C. overnight. The resultingresidue was concentrated and then ethyl acetate and ice-water were addedto the residue and the pH was adjusted to pH 7.5 by addition ofsaturated sodium bicarbonate solution. The product was extracted withethyl acetate and the extracts were washed with water, dried over sodiumsulfate, concentrated and purified by silica gel column chromatographyto yield methyl2-methyl-6-(trifluoromethoxy)benzo[d]thiazole-4-carboxylate.

f)3-(2,3-Dimethyl-4-{[2-methyl-6-(trifluoromethoxy)-1,3-benzothiazol-4-yl]methoxy}phenyl)propanoicacid

The title compound was prepared by reacting methyl2-methyl-6-(trifluoromethoxy)benzo[d]thiazole-4-carboxylate according tothe procedure as described in Example 83.

¹H NMR (MeOH) δ: 7.70 (s, 1H), 7.57 (s, 1H), 6.99 (d, J=8.1 Hz, 1H),6.83 (d, J=8.6 Hz, 1H), 5.57 (s, 2H), 2.90-2.97 (m, 2H), 2.89 (s, 3H),2.49-2.57 (m, 2H), 2.30 (s, 3H), 2.27 (s, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₁H₂₀F₃NO₄S, 439.1 (M+H), found 440.0.

Example 1193-(5-Bromo-4-{[3-bromo-2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

a) Ethyl3-(5-bromo-4-((3-bromo-2-methyl-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate

To a mixture of ethyl3-(2,3-dimethyl-4-((2-methyl-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)phenyl)propanoate(0.25 g, 0.55 mmol, prepared as described in Example 99) and sodiumacetate (0.05 g, 0.61 mmol) in acetic acid (1.3 mL) cooled in an icebath was added bromine (0.06 mL, 1.11 mmol) dropwise. After the mixturewas stirred for 30 min the resulting solution was concentrated underreduced pressure, the resulting oil was taken up in ethyl acetate,washed successively with aqueous 5% NaHSO₃, water, and dried overanhydrous magnesium sulfate. The filtrate was concentrated, and theresidue was purified by column chromatography to yield ethyl3-(5-bromo-4-((3-bromo-2-methyl-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate.

b)3-(5-Bromo-4-{[3-bromo-2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid

The title compound was prepared by reacting ethyl3-(5-bromo-4-((3-bromo-2-methyl-5-(trifluoromethoxy)benzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoateaccording to the procedure as described in Example 1.

¹H NMR (CHLOROFORM-d) δ: 7.42 (s, 1H), 7.27-7.30 (m, 2H), 5.16 (s, 2H),2.89-2.99 (m, 2H), 2.62 (t, J=7.8 Hz, 2H), 2.49 (s, 3H), 2.23 (s, 3H),2.18 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₁₉Br₂F₃O₅,601/603 (M+Na), found 601/603.

Biological Example 1

Human GPR120 DiscoveRx PathHunter Beta-Arrestin Assay

Assay Principle:

The binding of an agonist (medium/long chain fatty acids or smallmolecule agonists) to the G-protein-coupled receptor GPR120 activatesphospholipase C, leading to release of intracellular Ca⁺² through thegeneration of inositol 1,4,5-trisphosphate (InsP3 or IP3). GPR120activation can also trigger intracellular signaling via recruitment ofβ-Arrestin. In the present method, agonist-induced activation of thehuman GPR120 receptor is monitored through the use of PathHunter CHO-K1GPR120 β-Arrestin Cell Line engineered by DiscoveRx, as detailed below.The cell lines are designed to co-express both the ProLink/Enzyme Donor(PK)-tagged GPCR and the Enzyme Activator (EA)-tagged β-Arrestin fusionproteins. Upon GPR120 receptor stimulation/activation, the EA-taggedβ-Arrestin portion is translocated to the tagged receptor, where the twoenzyme fragments are brought within close proximity. Under theseconditions, these fragments can interact and form an active Beta-galenzyme complex through Enzyme Fragment Complementation (EFC). Thisactive Beta-gal complex can enzymatically hydrolyse the substrate toproduce a detectable light signal therefore, activation as a function ofagonist concentration can be expressed as an EC₅₀ value to determinerelative compound activities. This in vitro assay therefore serves toassess compound agonist activity of the GPR120.

Procedure β-Arrestin A:

In Procedure β-arrestin A, the cell used were PathHunter CHO-K1 GPR120β-Arrestin Cell Line, expressing the long form of human GPR120 (Genbankaccession number NM_181745), with 3000 cells per well.

Procedure β-Arrestin B:

In Procedure β-arrestin B the cells used were PathHunter CHO-K1 GPR120Sβ-Arrestin Cell Line, expressing the short form of the GPR120 receptor(Accession #NM_181745), with 5000 cells/well.

Assay Procedure:

The selected CHO-K1 GPR120 β-Arrestin cells were cultured in Ham's F12media supplemented with 10% fetal bovine serum (FBS), 1% Glutamine, 1×p/s, 800 μg/ml G418 and 300 μg/ml Hygromycin B (for selection). Cellstocks were maintained and grown in a sub-confluent state using standardcell culture procedures. The day before the experiment, the cells wereharvested with non-enzymatic cell dissociation buffer and re-suspendedin complete growth media at the desired concentration. A Corning384-plate was then seeded with the proper number of cells in a volume of25 μL, per well. The seeded plates were incubated overnight at 37° C.

On the day of the experiment, the Assay Buffer containing (a) HBSS withCa⁺⁺ and Mg⁺⁺, (b) 20 mM HEPES, and (c) 0.1% BSA stabilizer (pH 7.4) wasprepared. The growth medium was gently removed from the cell plates and20μL of Assay Buffer added to each well. The plate was then incubated at37° C. for 60 mins. Test compounds were serially diluted in Assay Bufferto desired concentrations (more particularly, to one or more of thefollowing μM concentrations: 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.562μM, 0.781 μM, 0.391 μM, 0.195 μM, 0.098 μM, 0.049 μM, 0.024 μM, 0.012μM). Five μl of compound dilution was then added to each well and theplate incubated at 37° C. for 90 mins. The detection reagents wereprepared according to the manufacture's instruction. Twelve μL of thedetection reagents were added to each well and the plate incubated atroom temperature for 60 mins.

The plates were read on an EnVision instrument, using Protocol name:Luminescence, Plate type: 384 Costar, Measurement height: 3 mm,Measurement time: 1 s, Aperture: 384 Plate aperture. The % activityrelative to the positive control was calculated using the followingequation:

${\% \mspace{14mu} {Activity}} = {\frac{{Count}_{compound} - {Count}_{vehicle}}{{Count}_{{positive}\mspace{14mu} {control}} - {Count}_{vehicle}} \times 100\%}$

The % Activity values were plotted versus the concentration of testcompound and fitted to a sigmoidal dose-response curve with a Hillslope=1 (fixed value) using nonlinear regression with GraphPad Prism 5.0to calculate the EC₅₀ values. The Fitting Equation was:Y=Bottom+(Top−Bottom)/(1+10̂((Log EC₅₀−X)*HillSlope)), where X is the logof the concentration and Y is the response.

Biological Example 2 In Vitro Assay Human GPR120 in Calcium Flux AssayAssay Principle

This in vitro assay serves to assess test compound agonist activityagainst the short splice variant (SVS with Accession numberNM_001195755.1 confirmed by sequencing data) of the GPR120 receptor. TheHuman Short splice variant #2 (NM_001195755.1) is missing an in-framecoding exon compared to variant 1 (the Human Long splice variantNM_181745.3), resulting in a shorter isoform (GPR120-S) lacking a 16 aaprotein segment compared to isoform GPR120-L. The assay platformutilizes HEK-293 cells stably transfected to express the Human GPR120short form. These cells are first loaded with the Ca⁺² sensitive dye,Fluo-4 NW. Upon stimulation, intracellular released Ca⁺² can bind to thedye and alter its fluorescence intensity. This increase in fluorescencesignal, and thus the flux in intracellular [Ca²⁺], is detected andquantitated by fluorescence imaging using a FLIPR reader. The effect ofthe agonist is measured as a function of concentration and used tocalculate an EC₅₀ based upon a response curve.

Procedure Calcium A:

In this procedure 2500 cells/well were employed.

Procedure Calcium B:

In this procedure 4200 cells/well were employed.

Assay Procedure:

A Human GPR120 clone (Genbank accession number NM_001195755.1) wasplaced into the pcDNA3.1 mammalian expression vector carrying theneomycin resistance gene. A stable mammalian cell was generated byplacing the above clone into a HEK293 background. Clonal cellsresponding to long chain fatty acids had expression levels of GPR120confirmed by RT-qPCR. Human HEK-GPR120 cells were cultured in Dulbecco'sModified Eagle's Medium (DMEM)/F12 medium supplemented with 10% fetalbovine serum (FBS), 1% L-Glutamine and 1% penicillin/streptomycin and0.5 mg/ml G-418. Cells were split 2 times a week to keep the cells inthe log-phase growth.

In preparation for the assay, HEK cells stably transfected with HumanGPR120 (2.5K cells per well in 25 uL growth medium) were seeded into384-well plates and then incubated overnight (37° C., 5% CO₂). The nextday, the media was changed to 20 μl assay buffer and the cell starvedfor 1 h at 37° C. The dye loading solution (2× dye) was prepared using10 ml assay buffer, 100 μl of 250 mM probenecid, 1 bottle of ComponentA, and 20 μl of dye in DMSO. Twenty μl of the 2× dye loading buffer wasthen added to each well. The plates were incubated at 37° C. for 30 min,then at room temperature for an additional 15 minutes, before performingthe assay on FLIPR.

Test compounds were prepared in assay buffer (2 μl of test compound+198μl assay buffer, final DMSO in assay plate is 0.2%) at the desiredconcentration, more particularly at 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25μM, 3.125 μM, 1.562 μM, 0.781 μM, 0.391 μM, 0.195 μM, 0.098 μM, 0.049μM, 0.024 μM and 0.012 μM.

The assay was performed on a FLIPR plate reader using the followingparameters. Baseline was read for 10 seconds at 1 sec intervals. Theprogram was set to transfer 10μL of ligand from compound plate to cellplate after baseline reading. Aspiration was executed at: 10 μl/secspeed, 4.6 μl height; Dispensing was executed at: 30 μ/sec speed, 45 μlheight. After compound addition, each well was read for 300 sec, withmeasurements collected at 1 sec intervals.

The kinetic data from the FLIPR was based upon a 5 minute window fordata collection. The fluorescence of each sample well was used forindividual calculations of a normalized RFU value, which was defined asmaximum response minus the minimum response. The normalized fluorescencereading (RFU) was calculated as follows:

RFU=Fmax−Fmin

The data were fitted to a sigmoidal dose-response curve with a variableHill slope (<2) using nonlinear regression with GraphPad Prism 5.0 tocalculate the EC₅₀ values. The Fitting Equation was:Y=Bottom+(Top−Bottom)/(1+10̂((Log EC₅₀−X)*HillSlope)), where X is the logof the concentration and Y is the response.

Representative compounds of formula (I) were tested according toprocedure as described in Biological Example 1 and 2, above, withresults as listed in Table 6 below.

TABLE 6 GPR120 EC₅₀ (μM) B-arrestin A B-arrestin B Calcium A Calcium BID No EC₅₀ (μM) EC₅₀ (μM) EC₅₀ (μM) EC₅₀ (μM) 1 >19.9986 2 0.374 0.051 30.327 0.058 4 5.206 0.279 5 0.949 1.241 6 >19.9986 7 0.108 0.124 8 0.6130.297 9 2.750 10 0.424 11 0.283 0.094 0.023 12 0.151 0.070 0.039 130.302 14 1.315 15 4.754 17 0.455 0.345 18 1.666 0.653 19 1.681 20 5.28621 0.458 0.159 22 0.797 0.166 23 0.470 0.339 29 0.616 0.107 30 0.759 310.232 0.044 32 2.907 0.277 33 1.107 34 1.015 35 0.190 0.040 36 0.0850.069 0.010 0.012 37 0.271 0.043 38 0.028 40 0.107 0.034 41 0.626 0.29144 0.230 0.027 45 0.095 0.024 47 0.197 0.022 49 0.507 0.237 50 0.4960.059 51 0.392 52 0.374 0.029 53 0.673 54 0.429 0.150 0.036 55 0.0730.028 57 0.077 0.017 58 0.410 0.087 59 0.146 0.093 60 0.706 0.162 610.190 0.024 62 0.274 0.067 63 0.231 0.067 64 0.271 0.056 65 0.240 0.09666 1.412 0.077 67 0.221 0.093 69 0.223 0.045 70 2.499 1.291 0.162 710.045 0.064 75 0.394 0.182 76 0.144 0.020 77 0.176 0.028 78 0.121 0.02079 2.225 80 0.249 0.151 81 0.817 0.136 82 0.851 0.153 83 0.440 0.051 840.434 0.131 85 0.238 0.015 86 0.460 0.207 87 0.409 0.079 88 0.594 0.14789 0.119 0.017 90 0.532 0.113 91 0.629 1.915 92 0.417 93 0.536 1.598 940.274 95 0.134 96 0.148 0.030 97 0.169 0.020 98 0.154 0.018 99 >5.00034100 >5.00034 101 3.200 102 >5.00034 103 2.998 104 1.549 1.883 0.499 1050.402 0.204 0.091 106 0.882 0.184 107 3.917 1.012 108 2.737 109 0.1910.038 110 3.309 0.949 111 0.299 0.107 112 0.110 0.121 115 0.772 0.468117 0.681 0.422 118 0.237 0.065 119 1.439 120 1.543 121 1.188 0.382 1231.415

Biological Example 3 In Vivo Assay GPR120 DIO Mice OGTT Screening

18-22 week old, C571316 mice on a high fat diet (60% HFD) for 12-16weeks (ave. body weight ˜37-41 g) were fasted for 6 hr, with removal offood occurring at 7 am on the morning of the study. The animals weresorted into treatment groups the day before the study by body weight.Animals outside the bounds of ˜30-50 g were left out of the study. Theanimals had been handled and shammed a total of 5-8 days (1-3 daysimmediately prior to the study). Glucose (in 1 ml syringes) was drawn upthe morning of the study. Test compounds were kept spinning and wereonly drawn into 1 ml syringes prior to study commencement. Animals werebled via tail snip to determine basal glucose levels prior to dosing oftreatments. An Ascensia BREEZE Blood Glucose Monitoring System by Bayerwas used for determining glucose levels.

Animals were moved into the testing room at ˜9-11 am, to yield them timeto acclimate. The bleeds and dosing started at approximately 1 pm in30-second intervals per animal. All groups were dosed 30 minutes priorto glucose administration at a dose volume of 10 ml/kg (the dose volumewas calculated separately for each individual animal). Test compoundswere administered at one or more of the following dosages: 0.1 mg/kg,0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg.

Thirty minutes after the first dose (with test compound) animals werebled again for a second baseline, or T=0, and immediately dosed withglucose (20% solution; TEKNOVA, 250 ml sterile bottle w/ cataloguenumber G0525) via a PO injection. The exact dose volume for glucose wasalso calculated separately for each individual animal.

Blood glucose was measured at 15, 30, 45, 60, and 90 minutespost-glucose administration via the snipped tail. If an animal reached avalue of “HI”, the upper limit of the glucometer (600mg/dl) wassubstituted as the blood glucose value and the study was analyzed asnormal with no exclusions. If 50% or more of any treatment group reachesa “HI” value at least once, the study was considered invalid andrepeated. Glucose values were typed into an EXCEL spreadsheet where theywere used to calculate glucose AUC and delta AUC post-compound andpost-glucose. The glucose excursion curves and the different versions ofthe AUC's were graphed in GraphPad Prism 5.

Statistical Methods:

Note: All statistics completed in this study were completed using thestatistical software package GraphPad Prism 5. Standard procedures foranalyzing data sets from screening GPR120 compounds in DIO mouse OGTT'swere as listed here below. In addition to the statistics that were runusing GraphPad Prism 5, Microsoft Excel was used to calculate thepercent changes in AUC from vehicle groups as detailed below.

Change from −30 to 0 BSLN Glucose, Raw Glucose AUC −30 to 90 min, DeltaGlucose AUC −30 to 90 min, Raw Glucose AUC 0 to 90 min, Delta GlucoseAUC 0 to 90 min were analyzed using Column Statistics Analysis, withmean values used to calculate % change from the vehicle mean group, aswell as mean, SEM and/or % change from vehicle, where appropriate; andusing One-Way ANOVA w/ a Tukey Post-Test (Comparing All Pairs ofColumns) with each treatment group examined to see if it wasstatistically significant compared to vehicle (*=P<0.05, **=P<0.01,***=P<0.001).

Representative compounds of the present invention were tested accordingto the procedure as described in Biological Example 2, with results aslisted in Table 7, below.

TABLE 7 GPR120 DIO OGTT Results DIO Lowering Glucose AUC ID No. (−30 to90) @ 10 mg/kg 11 −0.39 12 −0.70 31 −0.67 37 0.03 44 0.07 52 0.03 55−0.41 75 −31% 85 −37% 98 −0.33

Biological Example 4 In Vivo Assays A: GPR120 C57bl6 Mouse IPGTT

Male, C57bl/6J Mice were ordered in at 8 weeks of age from Jackson Labs.Individual mice weighed anywhere in the range of 25-30 grams on studyday. The mice were fasted, with removal of food occurring at 7 am on themorning of the study. Animals were moved into the room at 10:00 am, togive them time to acclimate. Glucose (insulin syringes) was drawn upeither the night before or the morning of the study. Glucose was dosed(IP) at 1.5 g/kg at 7.5 ml/kg (20% glucose straight TEKNOVA, 250 mlsterile bottle w/ catalogue number G0525). Test compounds were keptspinning and were only drawn into the syringes prior to studycommencement. Animals were bled via tail snip to determine basal glucoselevels prior to dosing of treatments. An Ascensia BREEZE Blood GlucoseMonitoring System by Bayer (using unique 10-test disks) was used fordetermining glucose levels. The bleeds started at approximately 12:45 pmand dosing started, at 1-minute intervals, immediately after. All groupswere dosed 30 minutes prior to glucose administration at a dose volumeof 10 ml/kg (the dose volume was calculated separately for eachindividual animal). Thirty minutes after the first dose animals werebled again for a second baseline, or T=0, and immediately dosed withglucose via an i.p. injection. The exact dose volume for glucose wasalso calculated separately for each individual animal. Glucosemeasurements were taken at −30 min prior to compound dose, at t=0(immediately prior to glucose dose), and at 15, 30, 45, 60, 90 min postglucose dose.

Glucose values were entered into an Excel sheet and graphed in Graph PadPrism. The following were calculated from Prism: Change from −30 to 0BSLN Glucose, Raw Glucose AUC −30 to 90 min, Delta Glucose AUC −30 to 90min, Raw Glucose AUC 0 to 90 min, Delta Glucose AUC 0 to 90 min.

B: C57bl6 mouse OGTT:

The assay design is the same as that described above for the C57bl6mouse IPGTT. The difference is that glucose was dosed PO at 3g/kg, 7.5ml/kg of 40% glucose.

Representative compounds of the present invention were tested accordingto the procedures as described in Biological Example 3, above withresults as listed in Table 8, below. In the results presented below, thedesignation “nd” indicates that no numbers were reported (results werenot different from vehicle). Where a compound was tested more than once,each result is listed individually.

TABLE 8 GPR120 C57bl6 Mouse IPGTT and OGTT Results C57 IPGTT C57 OGTT IDno. 1 mg/kg 3 mg/kg 10 mg/kg 30 mg/kg 30 mg/kg 2 −50 2 −54 2 −64 −53 2−27 −52 2 −67 −40 2 −57 2 −32 2 −34 3 −35 4 nd 11 −39 12 −66 13 −38 22nd 27 −42 28 −45 29 nd 35 −47 35 −15 −28 −42 36 −54 40 −41 44 nd 45 −1547 −27 55 −14 55 −10 57 −25 58 −20 63 nd 71 −35 71 nd −12 −23 78 −21 87−13 88 −6 89 −11

The 057b16 Mouse IPGTT and OGTT dose response was measured forrepresentative compounds of the present invention, with results aslisted in Table 9, below.

TABLE 9 C57bl6 Mouse IPGTT and OGTT dose response ID No. 1 mg/kg 3 mg/kg10 mg/kg 30 mg/kg Dose Responses C57 IPGTT 2  −3% −20% −27% −53% 36  −7%−36% −46% 40 −28%  13% −34% Dose Responses C57 OGTT 2 −29% −31% −51% 3−15% −24% −35% 11 −30% −38% −43% 12  6% −26% −30% 13 −43% 13 −16% −16%−63%

Formulation Example 1 (Prophetic Example) Solid, Oral Dosage Form

As a specific embodiment of an oral composition, 100 mg of the Compound#85, prepared as in Example 53 is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula (I)

wherein

is selected from the group consisting of

R¹ is selected from the group consisting of cyano, C₁₋₆alkyl, -(hydroxysubstituted C₁₋₄alkyl), chloro substituted C₁₋₄alkyl, fluoro substitutedC₁₋₄alkyl, C₂₋₄alkenyl, chloro substituted C₂₋₄alkenyl, fluorosubstituted C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄alkyl)-O—(C₁₋₄alkyl),—(C₁₋₄alkyl)-SO—(C₁₋₄alkyl), —(C₁₋₄alkyl)-SO₂—(C₁₋₄alkyl),—(C₁₋₄alkyl)-NR^(A)R^(B), —(C₁₋₄alkyl)-NR^(A)—C(O)—(C₁₋₄alkyl),—(C₁₋₄alkyl)-NR^(A)—SO₂—(C₁₋₄alkyl), —C(O)OH, —C(O)O—(C₁₋₄alkyl),—C(O)—(C₁₋₄alkyl), —C(O)—NR^(A)R^(B), C₃₋₈cycloalkyl,—(C₁₋₄alkyl)-(C₃₋₈cycloalkyl), aryl and —(C₁₋₂alkyl)-(aryl); whereinR^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; R² is selected from the groupconsisting of hydrogen, halogen and C₁₋₄alkyl; R³ is selected from thegroup consisting of hydrogen, chloro and fluoro; R⁴ and R⁵ are eachindependently selected from the group consisting of hydrogen, halogen,cyano, C₁₋₄alkyl, chloro substituted C₁₋₄alkyl, fluoro substitutedC₁₋₄alkyl, C₂₋₄alkenyl, chloro substituted C₂₋₄alkenyl, fluorosubstituted C₂₋₄alkenyl, C₂₋₄alkynyl, chloro substituted C₂₋₄alkynyl,fluoro substituted C₂₋₄alkynyl, C₁₋₄alkoxy, fluoro substitutedC₁₋₄alkoxy, —O—(C₁₋₄alkyl)-O—(C₁₋₄alkyl), —(C₁₋₄alkyl)-O—(C₁₋₄alkyl),—(C₁₋₄alkyl)-SO₂—(C₁₋₄alkyl), —(C₂₋₄alkenyl)-SO₂—(C₁₋₄alkyl),—C(O)—NR^(C)R^(D), —O-(aryl) and —O—(C₁₋₂alkyl)-aryl; wherein R^(C) andR^(D) are each independently selected from the group consisting ofhydrogen and C₁₋₄alkyl; provided that at least one of R⁴ or R⁵ isselected from the group consisting of hydrogen, chloro and fluoro;alternatively, wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of

W is selected from the group consisting of C(R⁹); wherein R⁹ is selectedfrom the group consisting of hydrogen, fluoro and bromo; alternatively,wherein

W may be N; R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, cyano, C₁₋₆alkyl, chloro substitutedC₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, bromo substituted C₁₋₄alkyl,C₁₋₄alkoxy and fluoro substituted C₁₋₄alkoxy; alternatively, wherein

and W is C(R⁹), R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is selected from the group consisting of hydrogen, halogen, cyano,C₁₋₆alkyl, chloro substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl,bromo substituted C₁₋₄alkyl, C₁₋₄alkoxy, fluoro substituted C₁₋₄alkoxyand —(C₁₋₄alkyl)-C(O)OH; R⁰ is selected from the group consisting of—CH₂OH and —C(O)OH; or a pharmaceutically acceptable salt thereof.
 2. Acompound as in claim 1, wherein

is selected from the group consisting of

wherein R¹ is selected from the group consisting of cyano, C₁₋₆alkyl,-(hydroxy substituted fluoro substituted C₁₋₄alkyl, C₂₋₄alkenyl, fluorosubstituted C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄alkyl)-O—(C₁₋₄alkyl),—(C₁₋₄alkyl)-NR^(A)R^(B), —(C₁₋₄alkyl)-NR^(A)—C(O)—(C₁₋₄alkyl),—(C₁₋₄alkyl)-NR^(A)—SO₂—(C₁₋₄alkyl), —C(O)OH, —C(O)O—(C₁₋₄alkyl),—C(O)—(C₁₋₄alkyl), —C(O)—NR^(A)R^(B), C₃₋₆cycloalkyl,—(C₁₋₄alkyl)-(C₃-₆cycloalkyl), phenyl and —(C₁₋₂alkyl)-(phenyl); whereinR^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; R² is selected from the groupconsisting of hydrogen, halogen and C₁₋₄alkyl; R³ is selected from thegroup consisting of hydrogen, chloro and fluoro; R⁴ and R⁵ are eachindependently selected from the group consisting of hydrogen, halogen,cyano, C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, C₂₋₄alkenyl, fluorosubstituted C₂₋₄alkenyl, C₂₋₄alkynyl, fluoro substituted C₂₋₄alkynyl,C₁₋₄alkoxy, fluoro substituted C₁₋₄alkoxy, —O—(C₁₋₄alkyl)-O—(C₁₋₄alkyl),—(C₁₋₄alkyl)-O—(C₁₋₄alkyl), —(C₁₋₄alkyl)-SO₂—(C₁₋₄alkyl),—(C₂₋₄alkenyl)-SO₂—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), —O-(phenyl) and—O—(C₁₋₂alkyl)-(phenyl); wherein R^(C) and R^(D) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl; providedthat at least one of R⁴ or R⁵ is selected from the group consisting ofhydrogen, chloro and fluoro; alternatively, wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of

W is selected from the group consisting of C(R⁹); wherein R⁹ is selectedfrom the group consisting of hydrogen, fluoro and bromo; alternatively,wherein

W may be N; R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, cyano, C₁₋₆alkyl, fluoro substitutedC₁₋₄alkyl, C₁₋₄alkoxy and fluoro substituted C₁₋₄alkoxy; alternatively,wherein

and W is C(R⁹), R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is selected from the group consisting of hydrogen, halogen, cyano,C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, fluoro substitutedC₁₋₄alkoxy and —(C₁₋₄alkyl)-C(O)OH; R⁰ is selected from the groupconsisting of —CH₂OH and —C(O)OH; or a pharmaceutically acceptable saltthereof.
 3. A compound as in claim 2, wherein

is selected from the group consisting of

wherein R¹ is selected from the group consisting of cyano, C₁₋₄alkyl,-(hydroxy substituted C₁₋₂alkyl), fluoro substituted C₁₋₂alkyl, fluorosubstituted C₂₋₄alkenyl, —(C₁₋₂alkyl)-O—(C₁₋₂alkyl),—(C₁₋₂alkyl)-NR^(A)R^(B), —(C₁₋₂alkyl)-NR^(A)—C(O)—(C₁₋₂alkyl),—(C₁₋₂alkyl)-NR^(A)—SO₂—(C₁₋₂alkyl), —C(O)OH, —C(O)—(C₁₋₂alkyl),—C(O)—NR^(A)R^(B), C₅₋₆cycloalkyl, —(C₁₋₂alkyl)-(C₅₋₆cycloalkyl), phenyland —(C₁₋₂alkyl)-(phenyl); wherein R^(A) and R^(B) are eachindependently selected from the group consisting of hydrogen and methyl;R² is selected from the group consisting of hydrogen, halogen andC₁₋₂alkyl; R³ is selected from the group consisting of hydrogen, chloroand fluoro; R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, cyano, C₁₋₄alkyl, fluoro substitutedC₁₋₂alkyl, C₂₋₄alkynyl, fluoro substituted C₂₋₄alkynyl, C₁₋₄alkoxy,fluoro substituted C₁₋₄alkoxy, —O—(C₁₋₂alkyl)-O—(C₁₋₂alkyl),—(C₁₋₄alkyl)-SO₂—(C₁₋₂alkyl), —(C₂₋₄alkenyl)-SO₂—(C₁₋₂alkyl),—C(O)—NR^(C)R^(D), —O-(phenyl) and —O—(C₁₋₂alkyl)-(phenyl); whereinR^(C) and R^(D) are each independently selected from the groupconsisting of hydrogen and C₁₋₂alkyl; provided that at least one of R⁴or R⁵ is selected from the group consisting of hydrogen, chloro andfluoro; alternatively, wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of

W is selected from the group consisting of C(R⁹); wherein R⁹ is selectedfrom the group consisting of hydrogen, fluoro and bromo; alternatively,wherein

W may be N; R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, C₁₋₆alkyl, fluoro substituted C₁₋₂alkyland cyano; alternatively, wherein

and W is C(R⁹), R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is selected from the group consisting of hydrogen, C₁₋₂alkyl andfluoro substituted C₁₋₂alkyl; R⁰ is selected from the group consistingof —CH₂OH and —C(O)OH; or a pharmaceutically acceptable salt thereof. 4.A compound as in claim 3, wherein

is selected from the group consisting of

wherein R¹ is selected from the group consisting of cyano, methyl,ethyl, n-propyl, isopropyl, isopentyl, isobutyl, t-butyl,difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2-fluoro-ethen-1-yl,hydroxyl-methyl-, hydroxyl-ethyl-, methoxy-methyl-, methoxy-ethyl-,carboxy-, methyl-carbonyl-, aminocarbonyl-, dimethylamino-ethyl-,methyl-carbonyl-amino-ethyl-, methyl-sulfonyl-amino-ethyl-, cyclopentyl,cyclopentyl-methyl- and benzyl; R² is selected from the group consistingof hydrogen, fluoro, bromo and methyl; R³ is selected from the groupconsisting of hydrogen and fluoro; R⁴ is selected from the groupconsisting of hydrogen, chloro, fluoro, bromo, iodo,1,1,-difluoroeth-1-yl, ethynyl, prop-1yn-1-yl,3,3,3-trifluoroprop-1-yn-1-yl, trifluoromethyl, ethoxy, difluoromethoxy,trifluoromethoxy, cyano, dimethylaminocarbonyl-,3-(methylsulfonyl)-prop-1-yl and 3-(methylsulfonyl)-prop-1-yn-1-yl; R⁵is selected from the group consisting of hydrogen, fluoro, methyl,ethyl, methoxy, ethoxy, isopropyloxy, isobutyloxy,2,2,2-trifluoroethoxy, difluoromethoxy, phenyloxy, benzyloxy,methoxy-ethoxy- and 3-(methylsulfonyl)-prop-1-yl; provided that at leastone of R⁴ or R⁵ is selected from the group consisting of hydrogen,chloro and fluoro; alternatively, wherein

is selected from the group consisting of

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of

W is selected from the group consisting of C(R⁹); wherein R⁹ is selectedfrom the group consisting of hydrogen, fluoro and bromo; alternatively,wherein

is selected from the group consisting of

W may be N; R⁶ is selected from the group consisting of hydrogen,fluoro, methyl, and cyano; R⁷ is selected from the group consisting ofhydrogen, fluoro, methyl, n-propyl, isobutyl, isopentyl andtrifluoromethyl; alternatively, wherein

is selected from the group consisting of

and W is CH, R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is selected from the group consisting of hydrogen, methyl andtrifluoromethyl; R⁰ is selected from the group consisting of —CH₂OH and—C(O)OH; or a pharmaceutically acceptable salt thereof.
 5. A compound asin claim 4, wherein

is selected from the group consisting of

wherein R¹ is selected from the group consisting of cyano, methyl,ethyl, n-propyl, isopropyl, isobutyl, difluoromethyl, trifluoromethyl,2,2-difluoroethyl, 2-fluoro-ethen-1-yl, hydroxyl-ethyl-, methoxy-methyl-and methoxy-ethyl-; R² is selected from the group consisting of hydrogenand methyl; R³ is selected from the group consisting of hydrogen andfluoro; R⁴ is selected from group consisting of hydrogen, chloro,fluoro, bromo, iodo, trifluoromethyl, ethynyl, ethoxy, difluoromethoxy,trifluoromethoxy, prop-1-yn-1-yl and cyano; R⁵ is selected from thegroup consisting of hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy,isopropyloxy, isobutyloxy, 2,2,2-trifluoroethoxy, difluoromethoxy andmethoxy-ethoxy-; provided that at least one of R⁴ or R⁵ is selected fromthe group consisting of hydrogen, chloro and fluoro; alternatively,wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of

W is selected from the group consisting of C(R⁹); wherein R⁹ is selectedfrom the group consisting of hydrogen and fluoro; R⁶ is selected fromthe group consisting of hydrogen, fluoro, methyl and cyano; R⁷ isselected from the group consisting of hydrogen, fluoro, methyl,n-propyl, isopentyl and trifluoromethyl; alternatively, wherein

is selected from the group consisting of

and W is CH, R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is hydrogen; R⁰ is —C(O)OH; or a pharmaceutically acceptable saltthereof.
 6. A compound as in claim 4, wherein

is selected from the group consisting of

wherein R¹ is selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, 2,2-difluoroethyl, 2-fluoro-ethen-1-yl, andmethoxy-methyl-; R² is selected from the group consisting of hydrogenand methyl; R³ is selected from the group consisting of hydrogen andfluoro; R⁴ is selected from group consisting of hydrogen, chloro,fluoro, bromo, iodo, trifluoromethyl, ethynyl, ethoxy, difluoromethoxy,trifluoromethoxy, prop-1-yn-1-yl and cyano; R⁵ is selected from thegroup consisting of hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy,isopropyloxy, isobutyloxy, 2,2,2-trifluoroethoxy, difluoromethoxy andmethoxy-ethoxy-; provided that at least one of R⁴ or R⁵ is selected fromthe group consisting of hydrogen, chloro and fluoro; alternatively,wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of

W is selected from the group consisting of C(R⁹); wherein R⁹ is selectedfrom the group consisting of hydrogen and fluoro; R⁶ is selected fromthe group consisting of hydrogen, fluoro and methyl; R⁷ is selected fromthe group consisting of fluoro, methyl, n-propyl and trifluoromethyl;alternatively, wherein

is selected from the group consisting of

and W is CH, R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is hydrogen; R⁰ is —C(O)OH; or a pharmaceutically acceptable saltthereof.
 7. A compound as in claim 4, wherein

is selected from the group consisting of

wherein R¹ is selected from the group consisting of methyl, ethyl,n-propyl, 2,2-difluoroethyl and 2-fluoro-ethen-1-yl; R² is hydrogen; R³is selected from the group consisting of hydrogen and fluoro; R⁴ isselected from group consisting of hydrogen, chloro, fluoro, bromo, iodo,ethynyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy,prop-1-yn-1-yl and cyano; R⁵ is selected from the group consisting ofhydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, isopropyloxy,isobutyloxy, 2,2,2-trifluoroethoxy, difluoromethoxy and methoxy-ethoxy-;provided that at least one of R⁴ or R⁵ is selected from the groupconsisting of hydrogen, chloro and fluoro; alternatively, wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form

W is selected from the group consisting of C(R⁹); wherein R⁹ is selectedfrom the group consisting of hydrogen and fluoro; R⁶ is selected fromthe group consisting of hydrogen, fluoro and methyl; R⁷ is selected fromthe group consisting of fluoro, methyl and n-propyl; alternatively,wherein

is selected from the group consisting of

and W is CH, R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is hydrogen; R⁰ is —C(O)OH; or a pharmaceutically acceptable saltthereof.
 8. A compound as in claim 4, wherein

is selected from the group consisting of

wherein R¹ is selected from the group consisting of methyl, ethyl,n-propyl, 2,2-difluoroethyl and 2-fluoro-ethen-1-yl; R² is hydrogen; R³is hydrogen; R⁴ is selected from group consisting of chloro, bromo,iodo, ethynyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy andcyano; R⁵ is selected from the group consisting of hydrogen, methyl,ethyl, methoxy and difluoromethoxy; provided that at least one of R⁴ orR⁵ is selected from the group consisting of hydrogen and chloro;alternatively, wherein

R⁴ and R⁵ may be taken together with the carbon atoms to which they arebound to form

W is CH; R⁶ is methyl; R⁷ is methyl; alternatively, wherein

is selected from the group consisting of

and W is CH, R⁶ and R⁷ may be taken together with the carbon atoms towhich they are bound to form

R⁸ is hydrogen; R⁰ is —C(O)OH; or a pharmaceutically acceptable saltthereof.
 9. A compound as in claim 4, wherein

is selected from the group consisting of

wherein R¹ is selected from the group consisting of methyl, ethyl and2-fluoro-ethen-1-yl; R² is hydrogen; R³ is hydrogen; R⁴ is selected fromthe group consisting of chloro and trifluoromethoxy; R⁵ is selected fromthe group consisting of hydrogen and methyl; W is CH; R⁶ is methyl; R⁷is methyl; alternatively, R⁶ and R⁷ may be taken together with thecarbon atoms to which they are bound to form

R⁸ is hydrogen; R⁰ is —C(O)OH; or a pharmaceutically acceptable saltthereof.
 10. A compound as in claim 1, selected from the groupconsisting of3-{4-[(5-Chloro-2-ethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid;3-(2,3-Dimethyl-4-{[2-methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}phenyl)propanoicacid;3-(7-{[2-Methyl-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dihydro-1H-inden-4-yl)propanoicacid;3-{4-[(5-Chloro-2-methyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid;3-{4-[(5-Chloro-2,6-dimethyl-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoicacid;3-(4-{[2-(2-Fluoroethenyl)-5-(trifluoromethoxy)-1-benzofuran-7-yl]methoxy}-2,3-dimethylphenyl)propanoicacid;3-{4-[(6-Chloro-2-methyl-1,3-benzothiazol-4-yl)methoxy]-2,3-dimethylphenyl}propanoicacid; and pharmaceutically acceptable salts thereof.
 11. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of claim
 1. 12. A pharmaceutical composition madeby mixing a compound of claim 1 and a pharmaceutically acceptablecarrier.
 13. A process for making a pharmaceutical compositioncomprising mixing a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 14. A method of treating a disorder modulated by theGPR120 receptor, comprising administering to a subject in need thereof atherapeutically effective amount of the compound of claim
 1. 15. Themethod of claim 14, wherein the disorder modulated by the GPR120receptor is selected from the group consisting of obesity, obesityrelated disorders, impaired oral glucose tolerance, insulin resistance,Type II diabetes mellitus, metabolic syndrome, metabolic syndrome X,dyslipidemia, elevated LDL, elevated triglycerides, obesity inducedinflammation, osteoporosis and obesity related cardiovascular disorders.16. A method of treating a disorder selected from the group consistingof obesity, obesity related disorders, impaired oral glucose tolerance,insulin resistance, Type II diabetes mellitus, metabolic syndrome,metabolic syndrome X, dyslipidemia, elevated LDL, elevatedtriglycerides, obesity induced inflammation, osteoporosis and obesityrelated cardiovascular disorderscomprising administering to a subject inneed thereof a therapeutically effective amount of the composition ofclaim
 11. 17. A method of treating a condition selected from the groupconsisting of obesity, obesity related disorders, impaired oral glucosetolerance, insulin resistance, Type II diabetes mellitus, metabolicsyndrome, metabolic syndrome X, dyslipidemia, elevated LDL, elevatedtriglycerides, obesity induced inflammation, osteoporosis and obesityrelated cardiovascular disorderscomprising administering to a subject inneed thereof, a therapeutically effective amount of the compound ofclaim
 1. 18.-29. (canceled)